Pharmaceutical compositions

ABSTRACT

Methods and compositions are provided which comprise effective amounts of an analgesic to treat a subject, including reducing or eliminating an adverse effect associated with the analgesic.

CROSS-REFERENCE

This application is a continuation of U.S. application Ser. No.14/789,883, filed Jul. 1, 2015, which is continuation of U.S.application Ser. No. 14/036,946, filed on Sep. 25, 2013, now U.S. Pat.No. 9,226,901, which is a continuation of U.S. application Ser. No.13/347,552, filed on Jan. 10, 2012, now U.S. Pat. No. 9,198,867, whichis a continuation of U.S. application Ser. No. 12/351,704 filed on Jan.9, 2009, now U.S. Pat. No. 8,124,126, which claims the benefit of U.S.Provisional Application Nos. 61/020,139 filed Jan. 9, 2008, 61/043,037filed Apr. 7, 2008, and 61/060,758 filed Jun. 11, 2008, each of which isincorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

Available pain medications may have adverse effects, such as nausea,vomiting, and skin rashes and sedation. As a result of such adverseeffects, many subjects are unable to tolerate recommended dosages neededfor effective pain relief because of adverse effects. Accordingly, thereremains a need for effective therapeutics with reduced adverse effects.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 illustrates a chromatograph for example of a standard solution.

FIG. 2 illustrates one embodiment of a tablet of the invention. A.Illustrates a top view of the tablet (numerals in square brackets referto measurements in millimeters and numerals not in square brackets arein inches); B. illustrates a side view of the tablet (numerals in squarebrackets refer to measurements in millimeters and numerals not in squarebrackets are in inches).

FIG. 3 illustrates an example of chromatograph of a diluent blank andstandard solution.

FIG. 4 illustrates an example of a dissolution chromatograph for acomposition of the invention.

FIG. 5 illustrates an example of dissolution release profile for acomposition of the invention.

SUMMARY OF THE INVENTION

In one embodiment this invention provides compositions comprising (1) aneffective amount of: (a) an opioid analgesic; (b) a stimulant; (c) anantiemetic; and (2) a pharmaceutically acceptable carrier or vehicle.

In another embodiment this invention provides compositions comprising(1) an effective amount (a) oxycodone or a pharmaceutically acceptablesalt thereof, (b) promethazine or a pharmaceutically acceptable saltthereof, (c) modafinil or a pharmaceutically acceptable salt thereof and(d) naltrexone or a pharmaceutically acceptable salt thereof; and (2) apharmaceutically acceptable carrier or vehicle.

In another embodiment this invention provides compositions comprising(1) an effective amount of (a) morphine or a pharmaceutically acceptablesalt thereof, (b) promethazine or a pharmaceutically acceptable saltthereof, and (c) modafinil or a pharmaceutically acceptable saltthereof; and (2) a pharmaceutically acceptable carrier or vehicle.

In another embodiment this invention provides compositions comprising aneffective amount of butalbital or a pharmaceutically acceptable saltthereof, acetaminophen and promethazine or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable carrier or vehicle.

In another embodiment this invention provides compositions comprising(1) an effective amount of (a) an opioid analgesic agent; (b) ananti-emetic agent and (c) a beta blocker, serotonin receptor agonist,vasoconstrictor, anti-platelet agent, anti-convulsant, triptan, ergot,or calcitonin-gene-related peptide receptor antagonist; and (2) apharmaceutically acceptable carrier or vehicle.

In another embodiment this invention provides compositions comprising(1) an effective amount of (a) an opioid analgesic agent and (b)sumatriptan or a pharmaceutically acceptable salt thereof; and (2) apharmaceutically acceptable carrier or vehicle.

In another embodiment this invention provides compositions consisting of(1) an effective amount of (a) sumatriptan or a pharmaceuticallyacceptable salt thereof and (b) promethazine or a pharmaceuticallyacceptable salt thereof; and (2) a pharmaceutically acceptable carrieror vehicle.

In another embodiment this invention provides compositions comprising(1) an effective amount of (a) an opioid analgesic agent, (b) a Cox-2inhibitor agent, an anti-depressant agent, an anti-convulsant agent, ananti-cholinergic agent, an NMDA receptor antagonist agent, an anestheticagent or an α₂-adrenoreceptor agonist agent, (c) an opioid antagonistagent, (d) an agent that reduces or eliminates an adverse effect of theopioid agent; and (2) a pharmaceutically acceptable carrier or vehicle.

In another embodiment this invention provides compositions comprising(1) an effective amount of (a) an opioid analgesic agent, (b) anon-opioid analgesic agent, (c) cyclazacine or levallorphan; (d) anagent that reduces or eliminates an adverse effect of the opioidanalgesic agent; and (2) a pharmaceutically acceptable carrier.

In another embodiment this invention provides a composition comprising(1) an effective amount of (a) an opioid analgesic agent, (b) anon-opioid analgesic agent, (c) an antiemetic; (d) an abuse deterrentagent; and (2) a pharmaceutically acceptable carrier. In one embodimentthe abuse deterrent agent is niacin or a pharmaceutically acceptablesalt thereof; zinc sulfate; or sodium lauryl sulfate.

In another embodiment this invention provides compositions comprising(1) an effective amount of (a) an opioid analgesic agent, (b) anon-opioid analgesic agent, (c) an opioid antagonist agent, (d)aprepitant, perphenazine, acetylleucine monoethanolamine, azasetron,benzquinamide, bietanautine, bromopride, clebopride, diphenidol,methallatal, metopimazine, oxyperndyl, pipamazine, sulpiride,thiethylperazine, thioproperazine, or a pharmaceutically acceptable saltthereof; and (2) a pharmaceutically acceptable carrier or vehicle.

In another embodiment this invention provides bi-layer tabletscomprising: (1) a controlled-release layer comprising from about 6.5 mgto about 8.5 mg of hydrocodone or a pharmaceutically acceptable saltthereof; and from about 290 to about 360 mg of acetaminophen or apharmaceutically salt; and (2) an immediate-release layer comprisingfrom about 11 mg to about 14 mg of promethazine or a pharmaceuticallysalt thereof. In another embodiment this invention provides bilayertablets comprising (1) an effective amount of (a) an opioid analgesic ora pharmaceutically acceptable salt thereof and (b) one or moreantiemetic or a pharmaceutically acceptable salt thereof; and (2) apharmaceutically acceptable carrier or vehicle.

In another embodiment this invention provides bilayer tabletscomprising: (1) a controlled release layer comprising (a) from about 6.5mg to about 8.5 mg of hydrocodone or a pharmaceutically acceptable saltthereof, (b) from about 290 to about 360 mg of acetaminophen or apharmaceutically acceptable salt thereof, (c) from about 135 mg to about170 mg of silicified microcrystalline cellulose, (d) from about 17 mg toabout 23 mg of hydroxy methyl propyl cellulose, (e) from about 1 mg toabout 4 mg of magnesium stearate, and (f) from about 1 mg to about 4 mgof stearic acid; and (2) an immediate release layer comprising (a) fromabout 11 mg to about 14 mg of promethazine or a pharmaceuticallyacceptable salt thereof, (b) from about 100 mg to about 140 mg ofsilicified microcrystalline cellulose, (c) from about 12 mg to about 18mg of croscarmellose sodium and (d) from about 0.8 mg to about 1.5 mg ofmagnesium stearate.

In another embodiment this invention provides compositions comprising(1) an effective amount of (a) hydrocodone or a pharmaceuticallyacceptable salt thereof or oxycodone or a pharmaceutically acceptablesalt thereof; (b) acetaminophen or a pharmaceutically acceptable saltthereof, (c) promethazine or a pharmaceutically acceptable salt thereofand (d) about 0.75 mg of naltrexone or a pharmaceutically acceptablesalt thereof; and (2) a pharmaceutically acceptable carrier or vehicle.

In another embodiment this invention provides compositions consisting of(1) an effective amount of (a) oxycodone or a pharmaceuticallyacceptable salt thereof, (b) promethazine or a pharmaceuticallyacceptable salt thereof and (c) naltrexone or a pharmaceuticallyacceptable salt thereof; and (2) a pharmaceutically acceptable carrieror vehicle.

In another embodiment this invention provides compositions consisting of(1) an effective amount of (a) promethazine or a pharmaceuticallyacceptable salt thereof, (b) propoxyphene or a pharmaceuticallyacceptable salt thereof, (c) naproxen or a pharmaceutically acceptablesalt thereof; and (2) a pharmaceutically acceptable carrier or vehicle.

In another embodiment this invention provides methods for treating orpreventing pain, comprising administering to a subject in need thereofan effective amount of (a) an opioid analgesic agent, (b) an antiemeticagent or an antihistamine, and (c) a stimulant agent.

In another embodiment this invention provides methods for treating orpreventing a migraine headache comprising administering to a subject inneed thereof an effective amount of (a) an opioid analgesic agent; (b)an antiemetic agent; and (c) a stimulant agent.

In another embodiment this invention provides methods for treating orpreventing a headache comprising administering to a subject in needthereof an effective amount of (a) an opioid analgesic agent; and (b) anantiemetic agent. In one embodiment the headache is a migraine headache,cluster headache or hemicrania continua headache. In another embodimentthe headache is a chronic headache, tension headache or chronic tensionheadache.

In another embodiment this invention provides methods for treating pain,comprising administering to a subject in need thereof an effectiveamount of (a) an opioid analgesic agent, (b) an antiemetic agent; and(c) a non-opioid analgesic agent; wherein the subject is about 65 yearsof age or older.

In another embodiment this invention provides methods for treating orpreventing photophobia comprising administering to a subject in needthereof an effective amount of (a) an opioid analgesic agent; and (b) anantiemetic agent. In one embodiment the photophobia is associated withmigraine headache.

In another embodiment this invention provides methods for treating orpreventing headache comprising: administering to a subject in needthereof (1) an effective amount of (a) triptan or a pharmaceuticallyacceptable salt thereof and (b) promethazine or a pharmaceuticallyacceptable salt thereof; and (2) a pharmaceutically acceptable carrieror vehicle. In one embodiment the triptan is sumatriptan. In anotherembodiment the headache is migraine headache.

In another embodiment this invention provides methods for treating orpreventing pain comprising: administering to a subject in need thereof(1) an effective amount of (a) an opioid analgesic agent, (b) a Cox-2inhibitor agent, an anti-depressant agent, an anti-convulsant agent, ananti-cholinergic agent, an NMDA receptor antagonist agent, an anestheticagent or an α₂-adrenoreceptor agonist agent, (c) an opioid antagonistagent, (d) an agent that reduces or eliminates an adverse effect of theopioid agent; and (2) a pharmaceutically acceptable carrier or vehicle.

In another embodiment this invention provides methods for treating orpreventing pain comprising, administering to a subject in need thereof abi-layer tablet comprising: (1) a controlled-release layer comprisingfrom about 6.5 mg to about 8.5 mg of hydrocodone or a pharmaceuticallyacceptable salt thereof; and from about 290 to about 360 mg ofacetaminophen or a pharmaceutically salt; and (2) an immediate-releaselayer comprising from about 11 mg to about 14 mg of promethazine or apharmaceutically salt thereof.

In another embodiment this invention provides methods for treating orpreventing pain comprising, administering to a subject in need thereof abi-layer tablet comprising (1) an effective amount of (a) oxycodone or apharmaceutically acceptable salt thereof and (b) promethazine or apharmaceutically acceptable salt thereof; and (2) a pharmaceuticallyacceptable carrier or vehicle.

In another embodiment this invention provides methods for treating orpreventing pain comprising, administering to a subject in need thereof abi-layer tablet comprising: (1) a controlled release layer comprising(a) from about 6.5 mg to about 8.5 mg of hydrocodone or apharmaceutically acceptable salt thereof, (b) from about 290 to about360 mg of acetaminophen or a pharmaceutically acceptable salt thereof,(c) from about 135 mg to about 170 mg of silicified microcrystallinecellulose, (d) from about 17 mg to about 23 mg of hydroxy methyl propylcellulose, (e) from about 1 mg to about 4 mg of magnesium stearate, and(f) from about 1 mg to about 4 mg of stearic acid; and (2) an immediaterelease layer comprising (a) from about 11 mg to about 14 mg ofpromethazine or a pharmaceutically acceptable salt thereof, (b) fromabout 100 mg to about 140 mg of silicified microcrystalline cellulose,(c) from about 12 mg to about 18 mg of croscarmellose sodium and (d)from about 0.8 mg to about 1.5 mg of magnesium stearate.

In another embodiment this invention provides methods for treating orpreventing pain comprising, administering to a subject in need thereofcomposition consisting of (1) an effective amount of (a) promethazine ora pharmaceutically acceptable salt thereof, (b) propoxyphene or apharmaceutically acceptable salt thereof, (c) naproxen or apharmaceutically acceptable salt thereof; and (2) a pharmaceuticallyacceptable carrier or vehicle.

In one embodiment of the invention, a composition is in the form of abilayer tablet, wherein the bilayer tablet comprises animmediate-release layer and a controlled-release layer, wherein eachlayer comprises one or more pharmaceutically active agents disclosedherein.

In yet another embodiment of the invention a bilayer tablet comprises aneffective amount of an antiemetic and the antiemetic is capable ofachieving from about 70% to about 80% dissolution in the stomach of asubject in about 5 to about 10 minutes following oral administration.

In another embodiment of the invention a bilayer tablet comprises aneffective amount of an opioid analgesic, or a non-opioid analgesic, andthe opioid analgesic or the non-opioid analgesic is capable of achievingfrom about 30% to about 60% dissolution in the stomach of a subject inabout 5 to about 10 minutes following oral administration.

DETAILED DESCRIPTION OF THE INVENTION

All patents and publications and referred to herein are incorporated byreference in their entirety.

The invention is generally directed to compositions comprising multiplepharmaceutically active agents that are useful as therapeutics thatalleviate, abate or eliminate one or more conditions in a subject inneed thereof, as further described herein below.

An “effective amount” of when used in connection with composition of theinvention is an amount sufficient to produce a therapeutic result in asubject in need thereof. For example a therapeutic result can include,but is not limited to, treating or preventing pain, nausea or vomitingby a subject.

An “effective amount” when used in connection with an opioid analgesicagent alone or in combination is an amount that is effective fortreating or preventing pain, wherein the antagonist agent is provided incombination with one or more pharmaceutically active agents disclosedherein. In one embodiment, the one or more pharmaceutically active agentis an antiemetic.

An “effective amount” when used in connection with an antiemetic agentis an amount that is effective for preventing or reducing or eliminatingone or more adverse effects associated with one or more pharmaceuticallyactive agent disclosed herein. In various embodiments, the one or morepharmaceutically active agent includes but is not limited to an opioidanalgesic and/or a non-opioid analgesic.

In further embodiments, such adverse effects which are reduced,prevented or eliminated include but are not limited to incidence ofnausea or vomiting. Furthermore, an “effective amount” when used inconnection with an antihistamine is an amount that is effective forpreventing or reducing the incidence of nausea or vomiting, orpreventing or reducing adverse effects associated with an opioidanalgesic (e.g., opioid-induced nausea and vomiting).

An “effective amount” when used in connection with a stimulant agent isan amount that is effective to increase alertness, or lessen soporificeffects of an opioid agent, wherein the stimulant agent is present in adosage formulation alone or in combination with one or morepharmaceutically active agent disclosed herein. In various embodiments,the one or more pharmaceutically active agent includes but is notlimited to an antiemetic agent, and a barbiturate.

An “effective amount” when used in connection with a barbiturate agentis an amount that is effective for treating or preventing pain,producing a sedative effect, anesthetic effect or calming effect whenprovided alone or in combination with one or more pharmaceuticallyactive agent disclosed herein. In various embodiments, the one or morepharmaceutically active agent includes but is not limited to an opioidanalgesic, a non-opioid analgesic, antiemetic or combination thereof.

An “effective amount” when used in connection with a opioid antagonistagent is an amount that is effective for preventing or inhibiting abuseof a dosage form comprising an opioid analgesic agent, wherein theantagonist agent is provided in combination with one or morepharmaceutically active agent disclosed herein. In various embodiments,the one or more pharmaceutically active agent includes but is notlimited to an opioid agent, a non-opioid analgesic, a stimulant, abarbiturate, or a combination thereof.

An “effective amount” when in used in connection with one or more of theagents disclosed herein is the total amount of one or more of the agentsthat is useful for the treatment of pain.

The term “about” means the referenced numeric indication plus or minus10% of that referenced numeric indication.

Pharmaceutically active agents disclosed herein are capable of use in acomposition of the invention. A pharmaceutically active agent, such asan opioid analgesic agent, non-opioid analgesic agent, antitussiveagent, antiemetic agent, antihistamine, a stimulant, or a barbiturate,can be in the form of a pharmaceutically acceptable salt thereof.

In some embodiments of the invention a composition comprises ananalgesic agent (e.g., one analgesic or two, three or more analgesics)and agent (e.g., one, two or more of an antihistamine or antiemetic)that reduces or eliminates an adverse effect of an analgesic agent. Invarious embodiments, a composition of the invention comprises one ormore pharmaceutically active agents provided in Table 1 or Table 2, or apharmaceutically acceptable salt thereof.

In one embodiment, a composition comprise, an effective amount of anopioid analgesic agent, an effective amount of non-opioid analgesicagent, and an effective amount of an agent that reduces or eliminates anadverse effect of an analgesic agent.

In another embodiment of the invention a composition comprises anantiemetic and about 70 to about 80% of the antiemetic dissolves in thestomach of a subject after about 5 to about 10 minutes following oraladministration. In one embodiment, about 100% of the antiemeticdissolves in the stomach of a subject about 40, about 50 or about 60minutes following oral administration. In one embodiment, the antiemeticis promethazine or a pharmaceutically acceptable salt thereof. Inanother embodiment, the promethazine salt is promethazine HCl.

In another embodiment of the invention a composition comprises an opioidanalgesic and from about 30% to about 40% of the opioid analgesicdissolves in the stomach of a subject after about 5 to about 10 minutesfollowing oral administration. In one embodiment, about 100% of theopioid analgesic dissolves in the stomach of a subject about 40, about50 or about 60 minutes following oral administration. In one embodiment,the opioid analgesic is hydrocodone, oxycodone or a pharmaceuticallyacceptable salt thereof. In another embodiment, the hydrocodone salt ishydrocodone bitartrate; or the oxycodone salt is oxycodone HCl.

In one embodiment, compositions of the invention are administered to asubject at about every 4 to about 6 hours, about every 12 hours, orabout every 24 hours. In one embodiment, a composition of the inventionis administered once daily.

In one embodiment, the agent that reduces or eliminates an adverseeffect is an antiemetic agent or antihistamine. In further embodiments,the adverse effect reduced or eliminated is associated with an opioidanalgesic. In an additional embodiment, the adverse effect is associatedwith a non-opioid analgesic.

In various embodiments, an agent that reduces or eliminates an adverseeffect of an opioid analgesic agent or a non-opioid analgesic agentincludes but is not limited to promethazine, dolasetron, granisetron,ondansetron, tropisetron, palonosetron, domperidone, droperidol,haloperidol, chlorpromazine, prochloperazine, metoclopramide,alizapride, cyclizine, diphenhydramine, dimenhydrinate, meclizine,hydroxyzine, cannabis, dronabinol, nabilone, midazolam, lorazepam,hyoscine, dexamethasone, trimethobenzamide, emetrol, and propofol or apharmaceutically acceptable salt thereof.

In one embodiment, a composition of the invention comprises a non-opioidanalgesic agent which is acetaminophen, ibuprofen, naproxen orflurbiprofen, or a pharmaceutically acceptable salt thereof. In oneembodiment the agent is naproxen sodium or magnesium.

In one embodiment, the opioid analgesic agent is hydrocodone oroxycodone, or a pharmaceutically acceptable salt thereofthiosemicarbazone, p-nitrophenylhydrazine, o-methyloxime, semicarbazone,or bis (methylcarbamate) derivative, (each of the foregoing being anopioid analgesic agent or derivative). In a further embodiment, theopioid analgesic agent is hydrocodone bitartrate or oxycodonehydrochloride.

In another embodiment the opioid analgesic agent is a naturallyoccurring opiate, such as an alkaloid occurring in the opium poppy. Inone embodiment the naturally occurring opiate is morphine, codeine,narcotine, papaverine, narceine, thebaine; or a pharmaceuticallyacceptable salt thereof.

In one embodiment, a composition comprises an effective amount of eachof an opioid analgesic, a non-opioid analgesic and an antiemetic orantihistamine, wherein the composition is capable of providing aneffective plasma concentration of the antihistamine prior to aneffective plasma concentrations of the opioid and the non-opioidanalgesic, post oral administration. For example, a compositioncomprising an effective amount of each of an opioid analgesic,non-opioid analgesic, and an antihistamine or antiemetic—provides aneffective plasma concentration of the latter antihistamine or antiemeticin about 1 to about 20 minutes, which is substantially earlier thaneffective plasma concentration of an analgesic, which can be from about20 minutes to about 12 hours. In one embodiment of the invention, acomposition comprises an effective amount of each of one or morepharmaceutically active agents disclosed herein. In one embodiment, thecomposition is a bilayer tablet comprising a controlled-release layerand an immediate-release layer.

In one embodiment about 70% to about 80% of a pharmaceutically activeagent is capable of achieving dissolution from the immediate-releaselayer at about 5 to about 10 minutes following oral administration. Inanother embodiment about 70% to about 80% of a pharmaceutically activeagent is capable of achieving dissolution from the immediate-releaselayer at about 5 to about 10 minutes following contact with adissolution fluid, such as the dissolution fluid described in Example15.

In another embodiment about 100% of a pharmaceutically active agent iscapable of achieving dissolution from the immediate-release layer atabout 40 minutes following oral administration. In another embodimentabout 100% to of a pharmaceutically active agent is capable of achievingdissolution from the immediate-release layer at about 40 minutesfollowing contact with a dissolution fluid, such as the dissolutionfluid described in Example 15.

In another embodiment about 30% to about 40% of a pharmaceuticallyactive agent is capable of achieving dissolution from thecontrolled-release layer at about 5 to about 10 minutes following oraladministration. In another embodiment about 30% to about 40% of apharmaceutically active agent is capable of achieving dissolution fromthe controlled-release layer at about 5 to about 10 minutes followingcontact with a dissolution fluid, such as the dissolution fluiddescribed in Example 15.

In another embodiment about 90% of a pharmaceutically active agent iscapable of achieving dissolution from the controlled-release layer atabout 60 minutes following oral administration. In another embodimentabout 90% of a pharmaceutically active agent is capable of achievingdissolution from the controlled-release layer at about 60 minutesfollowing contact with a dissolution fluid, such as the dissolutionfluid described in Example 15.

In yet another embodiment, from about 90 to about 100% of apharmaceutically active agent is capable of achieving dissolution fromthe immediate-release layer at about 40, about 50 or about 60 minutesfollowing oral administration. In yet another embodiment, from about 90to about 100% of a pharmaceutically active agent is capable of achievingdissolution from the immediate-release layer at about 40, about 50 orabout 60 minutes following contact with a dissolution fluid, such as thedissolution fluid described in Example 15.

In yet another embodiment, from about 90 to about 100% of apharmaceutically active agent is capable of achieving dissolution fromthe controlled-release layer at about 40, about 50 or about 60 minutesfollowing oral administration. In yet another embodiment, from about 90to about 100% of a pharmaceutically active agent is capable of achievingdissolution from the controlled-release layer at about 40, about 50 orabout 60 minutes following contact with a dissolution fluid, such as thedissolution fluid described in Example 15. An illustrative dissolutionprofile for a composition of the invention is depicted in FIG. 5.

In various embodiments, the composition is in the form of any oraldosage form disclosed herein, including but not limited to a pill,tablet, or capsule. In one embodiment, the composition is in the form ofa bilayer tablet having an immediate-release layer and acontrolled-release layer, wherein one or more pharmaceutically activeagents are present in the immediate-release layer and one or morepharmaceutically active agents are present in the controlled releaselayer. In another embodiment, the immediate-release layer comprises oneor more antiemetic, and the controlled-release layer comprises one ormore pharmaceutically active agents disclosed herein, but which are notan antiemetic or antihistamine. In a further embodiment, an antiemeticor antihistamine is present in both the immediate-release andcontrolled-release layer. In another embodiment, the immediate releaselayer comprises promethazine or a pharmaceutically acceptable saltthereof. In another embodiment, the promethazine salt is promethazineHCl. In another embodiment, the controlled-release layer comprises anopioid analgesic. In a further embodiment, the opioid analgesic ishydrocodone or oxycodone, or a pharmaceutically acceptable salt thereof.In one embodiment the hydrocodone salt is hydrocodone bitartrate. Inanother embodiment, the oxycodone salt is oxycodone HCl. In a furtherembodiment, the controlled-release layer further comprises one or morenon-opioid analgesic. In one embodiment, the non-opioid analgesic isacetaminophen or a pharmaceutically acceptable salt thereof. In oneembodiment, the composition is in a form that achieves a hardness offrom about 5 to about 15 kiloponds and has a thickness of about 5, about5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about9, about 9.5 or 10 mm. In one embodiment, the tablet has a hardness ofabout 9.5 kiloponds. In another embodiment, the tablet has a hardness ofabout 12.5 kiloponds. It will be understood that as to the kilopond andthickness measurements, increments of 0.1 decimal points are within thescope of the invention.

In one embodiment, the composition is capable of providing an effectiveplasma concentration of an antiemetic in about 1 minute to about 20minutes after administration to a subject. In another embodiment, theantiemetic is promethazine or a pharmaceutically acceptable saltthereof. In a further embodiment the salt is promethazine HCl.

In various embodiments, a composition comprises from about 1% to about20% by weight of an antihistamine; from about 10% to about 80% by weighta non-opioid analgesic; and from about 1% to about 20% by weight of anopioid analgesic. In some embodiments, the antihistamine ispromethazine, dolasetron, granisetron, ondansetron, tropisetron,palonosetron, domperidone, droperidol, haloperidol, chlorpromazine,prochloperazine, metoclopramide, alizapride, cyclizine, diphenhydramine,dimenhydrinate, meclizine, hydroxyzine, cannabis, dronabinol, nabilone,midazolam, lorazepam, hyoscine, dexamethasone, trimethobenzamide,emetrol, or propofol, or pharmaceutically acceptable salt thereof.

In one embodiment, the composition is capable providing an effectiveplasma concentration of promethazine or a pharmaceutically acceptablesalt thereof in about 1 minute to about 20 minutes after administrationto a subject.

In one embodiment, a method is provided for reducing or eliminating anadverse effect of an analgesic agent, comprising administering to asubject in need thereof a composition comprising an effective amount ofeach of an opioid analgesic agent, a non-opioid analgesic agent and anagent which reduces or eliminates a adverse effect of the analgesicagents.

In one embodiment, a method is provided for treating or preventing pain,comprising administering to a subject in need thereof an effectiveamount of a composition comprising an effective amount of each of anopioid analgesic, or a pharmaceutically acceptable salt thereof, anon-opioid analgesic, or a pharmaceutically acceptable salt thereof, andan agent which reduces a adverse effect associated with the opioid ornon-opioid analgesic agent. In one embodiment, the agent that reduces anadverse effect is an antiemetic or an antihistamine.

In another embodiment the pain is associated with cancer, chronic oracute pain, a headache, chronic headache, a migraine headache, asurgical procedure, acute or chronic physical injury, bone fracture or acrush injury, spinal cord injury, an inflammatory disease (e.g.,pancreatitis), a non-inflammatory neuropathic or dysfunctional paincondition, or a combination thereof. In one embodiment the subject is amammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow,pig, or non-human primate, such as a monkey, chimpanzee or baboon. Inone embodiment, the subject is a human. In one embodiment a stimulantthat has anti-sedative properties, which can bring pain relief to thesubject with reduced sedative effects common to some opioid analgesicformulations.

In some embodiments, the agent useful for reducing or eliminating anadverse effect associated with administration of an opioid or non-opioidanalgesic agent, is promethazine, dolasetron, granisetron, ondansetron,tropisetron, palonosetron, domperidone, droperidol, haloperidol,chlorpromazine, prochloperazine, metoclopramide, alizapride, cyclizine,diphenhydramine, dimenhydrinate, meclizine, hydroxyzine, cannabis,dronabinol, nabilone, midazolam, lorazepam, hyoscine, dexamethasone,trimethobenzamide, emetrol, or propofol, or pharmaceutically acceptablesalt thereof.

A composition can be in any form disclosed herein, such as a multi-layertablet (e.g., a bi-layer tablet). In one embodiment, the multi-layertablet is a bi-layer tablet that comprises: (a) an immediate-releaselayer that comprises an effective amount of an agent which reduces oreliminates an adverse effect of an opioid analgesic; and (b) acontrolled-release layer that comprises an effective amount of each ofan opioid analgesic agent and a non-opioid analgesic agent.

In one embodiment, the agent that reduces or eliminates an adverseeffect associated with administration of an opioid or non-opioidanalgesic agent is released in a subject at a substantially faster ratethan an opioid or non-opioid analgesic in a composition of theinvention. For example, in one embodiment, a plasma concentration of theagent that reduces or eliminates an adverse effect of an opioidanalgesic is achieved in about 1 minute to about 20 minutes followingoral administration, as compared with a plasma concentration of ananalgesic agent, which can be achieved in about 30 minutes to about 8hours following oral administration. In various embodiments, thecompositions of the invention comprise an agent that reduces oreliminates an adverse effect associated with administration of an opioidanalgesic or non-opioid analgesic, where the agent provides an effectiveplasma concentration in about 1 minute to about 20 minutes followingoral administration.

In one embodiment, the agent that reduces or eliminates an adverseeffect associated with an opioid or a non-opioid analgesic is anantihistamine or antiemetic. In various embodiments, As indicated above,compositions can comprise an antiemetic agent including, for example,aprepitant, dronabinol, perphenazine, palonosetron, trimethobenzamide,metoclopramide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron,hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron,benzquinamide, bietanautine, bromopride, buclizine, clebopride,cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,thioproperazine, tropisetron, droperidol, haloperidol, prochloperazine,metoclopramide, diphenhydramine, cannabis, midazolam, lorazepam,hyoscine, dexamethasone, emetrol, propofol and a pharmaceuticallyacceptable salt or mixtures thereof.

In one embodiment, a composition comprises an effective amount of anopioid analgesic agent, a non-opioid analgesic agent, and an agent thatreduces or eliminates an adverse effect associated with administrationof the opioid or non-opioid analgesic. An adverse effect of opioid ornon-opioid analgesic agents includes but is not limited to nausea,vomiting, other gastric upset, skin rash, an allergic reaction such asswelling, difficulty breathing, closing of throat, abdominal pain,unusual bleeding or bruising, sedation, CNS depression, or respiratorydepression. In one embodiment, the adverse effect that is reduced oreliminated is nausea, vomiting, constipation, or a combination thereof.

In a further embodiment, the opioid analgesic agent is, for example,hydrocodone, oxycodone propoxyphene, or fentanyl, or a pharmaceuticallyacceptable salt thereof; the non-opioid analgesic agent is, for example,acetaminophen, ibuprofen, ketoprofen, naproxen, or aspirin or apharmaceutically acceptable salt thereof; and the agent useful forpreventing and/or suppressing an adverse effect is, for example, anantihistamine such as promethazine or a pharmaceutically acceptable saltthereof. In one embodiment of the invention, the pharmaceuticallyacceptable salt of naproxen is naproxen sodium.

In one embodiment an opioid analgesic agent, a non-opioid analgesicagent and an agent that reduces or eliminates an adverse effect areformulated in a bi-layer tablet.

In one embodiment the bi-layer tablet comprises an immediate-releaselayer and a controlled-release layer. In another embodiment, theimmediate-release layer comprises one or more pharmaceutically activeagent disclosed in Table 1 or Table 2 and the control release layercomprise one or more pharmaceutically active agents disclosed in Table 1or Table 2. In a further embodiment, the immediate-release layercomprises an antiemetic or antihistamine and the controlled-releaselayer comprises an opioid analgesic, a barbiturate, a stimulant, atriptan or a combination thereof. An illustrative bilayer tablet isdepicted in FIG. 2. In one embodiment, a bilayer tablet of the inventionhas the dimensions as depicted in FIG. 2.

In another embodiment the compositions comprise an effective amount ofeach of an analgesic agent, an antitussive agent, and an agent thatreduces or eliminates an adverse effect of the analgesic agent or theantitussive agent. Under some embodiments the antitussive is also ananalgesic.

In some embodiments the compositions comprise acetaminophen, hydrocodoneor oxycodone, or a pharmaceutically acceptable salt thereof; and anantitussive agent such as dolasetron, domperidone, meclizine,dronabinol, a benzodiazepine, an anticholinergic, hydrocodone oroxycodone, or a pharmaceutically acceptable salt thereof.

In a further embodiment of this invention, the opioid analgesic agentis, for example, hydrocodone, or oxycodone or a pharmaceuticallyacceptable salt thereof; the non-opioid analgesic agent is, for example,acetaminophen, ibuprofen, ketoprofen, naproxen, lidocaine, or aspirin ora pharmaceutically acceptable salt thereof; the antiemetic agent is, forexample 5-HT₃ receptor antagonist, a dopamine antagonist, anantihistamine, a cannabinoid, benzodiazepines, an anticholinergic,wherein all or less than all of the total amount of the antiemetic agentis formulated for immediate-release.

Another embodiment of this invention is directed to methods for thetreatment of pain, comprising administering an effective amount of eachof an opioid analgesic agent, a non-opioid analgesic agent and an agentthat reduces or eliminates an adverse effect of the opioid analgesicagent to a subject in need thereof.

The methods allow for use of analgesics in populations at risk ofadverse effect such as nausea, vomiting, other gastric upsets, skinrashes, allergic reactions such as swelling, difficulty breathing,closing of throat, abdominal pain, unusual bleeding or bruising, skinrashes, sedation, CNS depression, or respiratory depression.

In one embodiment, the compositions comprise an effective amount of eachof an opioid analgesic, an antiemetic, and an opioid antagonist, thecomposition is capable of providing protection from a metabolicconsequence of vomiting, particularly severe vomiting, in a subjectparticularly prone to adverse effects associated with an opioidanalgesic. An example of metabolic consequence of vomiting isdehydration. In a further embodiment, the subject administered acomposition of the invention is about 55 years of age or older, about 60years of age or older, about 65 years of age or older, or about 70 yearsof age or older. In one embodiment, the composition administered to sucha subject comprises an opioid analgesic and one or more antiemeticagent. In one embodiment, the composition comprises oxycodone,promethazine, and naltrexone, or a pharmaceutically acceptable saltthereof.

In various embodiments, a dosage form of the invention provides aneffective plasma concentration of an antiemetic or antihistamine at fromabout 1 minute to about 20 minutes after administration, such as about 1min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11min, 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 min, 20min, 21 min, 22 min, 23 min, 24 min, 25 min. In some embodiments, therelease rate occurs at substantially faster as compared with releaserates for the analgesic agents. Therefore, in one embodiment, afteradministration to a subject, the antihistamine (e.g., promethazinedolasetron, granisetron, ondansetron, tropisetron, palonosetron,domperidone, droperidol, haloperidol, chlorpromazine, prochloperazine,metoclopramide, alizapride, cyclizine, diphenhydramine, dimenhydrinate,meclizine, hydroxyzine, cannabis, dronabinol, nabilone, midazolam,lorazepam, hyoscine, dexamethasone, trimethobenzamide, emetrol orpropofol, or a pharmaceutically acceptable salt thereof) is released oran effective plasma concentration of an antihistamine or antiemetic isachieved before release of the opioid or non-opioid analgesic.

In some embodiments, a dosage form of the invention provides aneffective plasma concentration of said opioid analgesic or saidnon-opioid analgesic at from about 20 minutes to about 24 hours afteradministration, such as about 20 minutes, 30 minutes, 40 minutes, 50minutes, 1 hr, 1.2 hrs, 1.4 hrs, 1.6 hrs, 1.8 hrs, 2 hrs, 2.2 hrs, 2.4hrs, 2.6 hrs, 2.8 hrs, 3 hrs, 3.2 hrs, 3.4 hrs, 3.6 hrs, 3.8 hrs, 4 hrs,5 hrs, 6 hrs, 7 hrs, 8 hrs, 9 hrs, 10 hrs, 11 hrs, 12 hrs, 13 hrs, 14hrs, 15 hrs, 16 hrs, 17 hrs, 18 hrs, 19 hrs, 20 hrs, 21 hrs, 22 hrs, 23hrs, or 24 hrs following administration.

In further embodiments, the opioid or non-opioid analgesic is present inan effective plasma concentration in a subject from about 1 hour to 24hour or 1 day to 30 days, including but not limited to 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 12, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29 or 30 days. In addition, administration of dosagecompositions can be effected through patch delivery systems which areknown in the art.

In one embodiment compositions comprise an effective amount of each ofan opioid analgesics, a non-opioid analgesic agent, an antihistamine,anti-psychotic, anti-anxiety agent, or other CNS depressant isadministered a reduced dosage of one or lessen and adverse effect (e.g.CNS depression). In another embodiment the dosage of one or more ofpharmaceutically active agents is adjusted according to the severity ofthe pain and the response of the subject.

In subjects having a terminal disease or chronic condition, painmanagement can be of a primary concern to the subject's quality of life.

In some of these subjects tolerance to opioid analgesics can developwith continued use. In one embodiment, adjustments are made to theamounts or time-release characteristics of the component of acomposition, such as a composition comprising an effective amount ofeach of an opioid analgesic, a non-opioid analgesic and anantihistamine. In this embodiment the adjustments can provide painrelief to a subject with tolerance to opioid analgesics. In oneembodiment the amount of the opioid analgesic may be increased in thecomposition. In another embodiment the time release characteristics ofthe opioid analgesic may be adjusted so as to change the ratio ofimmediate-release opioid analgesic to controlled-release opioidanalgesic.

In one embodiment, the compositions comprise: hydrocodone, oxycodone, ora pharmaceutically acceptable salt thereof, in a dosage range of fromabout 1.0 mg to about 200 mg; acetaminophen or a pharmaceuticallyacceptable salt thereof in a dosage range of from about 200 mg to about1000 mg; and, promethazine or a pharmaceutically acceptable salt thereofin a dosage range of from about 0.5 mg to about 100 mg.

In another embodiment, a compositions comprises: oxycodone or apharmaceutically acceptable salt thereof in a dosage range of from about10 mg to about 80 mg; Naltrexone or a pharmaceutically acceptable saltthereof in a dosage range of from about 0.5 mg to about 0.75 mg; and,promethazine or a pharmaceutically acceptable salt thereof in a dosagerange of from about 12.5 mg to about 50 mg.

In yet another embodiment, the compositions comprises: oxycodone or apharmaceutically acceptable salt thereof in a dosage range of from about10 mg to about 80 mg; and promethazine or a pharmaceutically acceptablesalt thereof in a dosage range of from about 12.5 mg to about 50 mg.These compositions can be formulated using conventional technologies toprovide for an extended time release over a desired dosage interval,such as 4 hours, 6 hours, 9 hours, 12 hours, or 24 hours. In anotherembodiment, the compositions comprise about 7.5 mg of hydrocodone, about325 mg of acetaminophen or a pharmaceutically acceptable salt thereof,and about 12.5 mg of promethazine or a pharmaceutically acceptable saltthereof.

In another embodiment, the compositions comprise about 7.5 mg ofoxycodone or a pharmaceutically acceptable salt thereof, about 325 mg ofacetaminophen or a pharmaceutically acceptable salt thereof, and about12.5 mg of promethazine or a pharmaceutically acceptable salt thereof.

In another embodiment compositions comprise an effective amount ofhydrocodone or oxycodone, or a pharmaceutically acceptable salt thereof;an effective amount of acetaminophen or a pharmaceutically acceptablesalt thereof; and an effective amount of promethazine or apharmaceutically acceptable salt thereof, combined in a single, oralpill, tablet or lollipop, form having dosage levels that can be safelydoubled for combating severe pain.

In a further embodiment all or less than the entire total amount of thepromethazine or a pharmaceutically acceptable salt thereof is formulatedfor immediate-release into the subject's blood stream.

In a further embodiment all or less than the entire amount of thehydrocodone or oxycodone, or a pharmaceutically acceptable salt thereofis formulated for controlled-release into the subject's body.

In various embodiments, the agents are formulated as a dosage form(e.g., tablet, capsule, gel, lollipop), parenteral, intraspinalinfusion, inhalation, nasal spray, transdermal patch, iontophoresistransport, absorbing gel, liquid, liquid tannate, suppositories,injection, I.V. drip, other formulation, or a combination thereof totreat subjects.

In another embodiment, the agents are formulated as single oral dosageform such as a tablet, capsule, cachet, soft gelatin capsule, hardgelatin capsule, extended release capsule, tannate tablet, oraldisintegrating tablet, multi-layer tablet, effervescent tablet, bead,liquid, oral suspension, chewable lozenge, oral solution, lozenge,lollipop, oral syrup, sterile packaged powder includingpharmaceutically-acceptable excipients, other oral dosage forms, or acombination thereof.

In another embodiment a composition of the invention comprises an agentin immediate-release, quick release, controlled-release, extendedrelease, other release formulations or patterns, or a combinationthereof.

In one embodiment, a composition of the invention comprises three activeagents, such as a decongestant, an antitussive, an expectorant, amucus-thinning drug, an analgesic or an antihistamine. For example, inone embodiment one of the agents is an antitussive such as, e.g.,codeine, dihydrocodeine, hydrocodone, dextromethorphan, dextrorphan, ora pharmaceutically acceptable salt thereof; the other agent is adecongestant such as, e.g., phenylephrine, pseudoephedrine, or apharmaceutically acceptable salt thereof; and the other agent is anexpectorant. One will recognize that an active agent may fit into morethan one category (e.g., hydrocodone is an antitussive and opioidanalgesic).

In any of the embodiments disclosed herein, a composition of theinvention can be administered using one or more different dosage formswhich are further described herein. For example, a compositioncomprising multiple active agents can be administered in solid,semi-solid, micro-emulsion, gel, patch or liquid form. Such dosage formsare further described herein. Examples of such dosage forms are known,such as tablet forms disclosed in U.S. Pat. Nos. 3,048,526, 3,108,046,4,786,505, 4,919,939, 4,950,484; gel forms disclosed in U.S. Pat. Nos.4,904,479, 6,482,435, 6,572,871, 5,013,726; patches for delivery ofpharmaceutical compositions such as those disclosed in U.S. Pat. Nos.5,741,510, 4,624,665, 4,626,539, 4,834,978, 6,469,227, 5,919,479,6,261,595, 6,303,142, 6,341,387, 6,465,006, 6,613,350, 6,780,426,7,094,228, 6,756,053; capsule forms disclosed in U.S. Pat. Nos.4,800,083, 4,532,126, 4,935,243, 6,258,380; liquid forms disclosed inU.S. Pat. Nos. 4,625,494, 4,478,822, 5,610,184; or I.V. forms disclosedin U.S. Pat. Nos. 4,871,353, 4,925,444, 5,484,406; each of which isincorporated herein by reference in its entirety.

Immediate-release refers to the release of an active agent substantiallyimmediately upon administration. In one embodiment, immediate-releaseresults in dissolution of an agent within 1-20 minutes after enteringthe stomach. Dissolution can be of all or less than the entire amount ofthe active agent. For example, dissolution of 100% of an agent(antihistamine or antiemetic) can occur in the prescribed time.Alternatively, dissolution of less than all of the agent can occur inabout 1 minute to about 20 minutes (e.g., dissolution of about 70%,about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%,about 99.5% or 99.9% of an agent).

In one embodiment, the compositions comprise an antiemetic in an amountcapable of achieving a serum level Cmax of from about 0.2 ng/mL to about1 ng/mL at a Tmax of from about 1 to about 6 hours following oraladministration. In one embodiment the antiemetic is promethazine or apharmaceutically acceptable salt thereof. In another embodiment, thepharmaceutically acceptable salt is promethazine HCl. In a furtherembodiment, the composition is a bilayer tablet that has an immediaterelease layer and a controlled-release layer. In yet a furtherembodiment, the controlled release layer comprises an opioid analgesicagent or a non-opioid analgesic agent. In a further embodiment theimmediate-release layer comprises promethazine or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the compositions comprise promethazine or apharmaceutically acceptable salt thereof in an amount capable ofachieving a serum level Cmax of about 0.46 ng/mL at a Tmax of about 2 toabout 3 hours following oral administration. In one embodiment, thepromethazine or a pharmaceutically acceptable salt is at a dose byweight in the composition of about 10 mg to about 15 mg. In anotherembodiment, the promethazine or pharmaceutically acceptable salt is at adose (by weight in the composition) of about 12.5 mg. In a furtherembodiment, the composition is in the form of a bilayer tablet that hasan immediate release layer and a controlled-release layer. In yetanother embodiment, the promethazine or a pharmaceutically acceptablesalt is the only pharmaceutically active agent in the immediate releaselayer of a bilayer tablet of the invention. In one embodiment, thepromethazine is promethazine HCl. In yet a further embodiment, thecontrolled release layer comprises an opioid analgesic agent or anon-opioid analgesic agent. In a further embodiment, the opioidanalgesic is the only pharmaceutically active agent in thecontrolled-release layer of a bilayer tablet, non-opioid analgesic isthe only pharmaceutically active agent in the controlled-release layerof a bilayer tablet or both the opioid analgesic and non-opioidanalgesic are the only pharmaceutically active agents of thecomposition.

In another embodiment, immediate-release occurs when there isdissolution of an agent within 1-20 minutes after oral administration.In another embodiment, immediate-release results in substantiallycomplete dissolution within about 1 hour following oral administration.In one embodiment, a composition of the invention is capable ofproviding about 80% dissolution of an antiemetic in about 5 minutes(e.g., FIG. 5).

In various embodiments, immediate-release occurs when there isdissolution of an agent within 1-20 minutes after administration.Dissolution can occur in a subject's stomach and/or intestine. Inanother embodiment, immediate-release results in complete or less thancomplete dissolution within about 1 hour following administration to asubject. In another embodiment, immediate-release results in complete orless than complete dissolution within about 1 hour following rectaladministration. When used in association with the dissolution profilesdiscussed herein, the term “immediate-release” refers to wherein all orless than the entire amount of a dosage form is dissolved.

In some embodiments, immediate-release is through inhalation, such thatdissolution occurs in a subject's lungs, as further described herein.Dissolution of less than all of an active includes but is not limited todissolution of about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%,99.1%, 99.2%, 99.35, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.99% of theactive agent. Methods for measuring dissolution profiles are known(e.g., Example 15, infra).

In terms of a composition of the invention, “controlled-release” refersto the release of at least one pharmaceutically active agent from adosage form at a particular desired point in time after the dosage formhas is administered to a subject. Generally, controlled-release includessustained but otherwise complete release. A sudden and total release inthe stomach at a desired and appointed time or a release in theintestines such as through the use of an enteric coating, are bothconsidered controlled-release. Controlled-release can occur at apredetermined time or in a predetermined place within the digestivetract. It is not meant to be a passive, uncontrolled process as inswallowing a normal tablet. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548;5,073,543; 5,639,476; 5,354,556; 5,733,556; 5,871,776; 5,902,632; and5,837,284 each of which is incorporated herein by reference in itsentirety.

A control release dosage form begins its release and continues thatrelease over an extended period of time. Release can occur beginningalmost immediately or can be sustained. Release can be constant, canincrease or decrease over time, can be pulsed, can be continuous orintermittent, and the like. Generally, however, the release of at leastone pharmaceutically active agent from a controlled-release dosage formwill exceed the amount of time of release of the drug taken as a normal,passive release tablet. Thus, for example, while all of at least onepharmaceutically active agent of an uncoated aspirin tablet should bereleased within, for example, four hours, a controlled-release dosageform could release a smaller amount of aspirin over a period of sixhours, 12 hours, or even longer. Controlled-release in accordance withthe compositions and methods described herein generally means that therelease occurs for a period of six hours or more, such as 12 hours ormore.

Extended-release, or sustained-release, refers to the release of anagent, from a composition or dosage form in which the agent is releasedaccording to a desired profile over an extended period of time. In oneembodiment, controlled-release results in dissolution of an agent within20-720 minutes after entering the stomach. In another embodiment,controlled-release occurs when there is dissolution of an agent within20-720 minutes after being swallowed. In another embodiment,controlled-release occurs when there is dissolution of an agent within20-720 minutes after entering the intestine. In another embodiment,controlled-release results in substantially complete dissolution afterat least 1 hour following administration. In another embodiment,controlled-release results in substantially complete dissolution afterat least 1 hour following oral administration. In another embodiment,controlled-release results in substantially complete dissolution afterat least 1 hour following rectal administration. For example,controlled-release compositions allow delivery of an agent to a subjectover an extended period of time according to a predetermined profile.Such release rates can provide therapeutically effective levels of agentfor an extended period of time and thereby provide a longer period ofpharmacologic or diagnostic response as compared with conventional rapidrelease dosage forms. Such longer periods of response provide for manyinherent benefits that are not achieved with immediate-release dosages.In using analgesics for treatments of chronic pain, controlled-releaseformulations can be used instead of conventional short-actingformulations. When used in connection with the dissolution profilesdiscussed herein, the term “controlled-release” refers to wherein all orless than all of the total amount of a dosage form, made according tomethods and compositions described herein, delivers an active agent overa period of time greater than 1 hour.

In one embodiment, controlled-release refers to delayed release of anagent, from a composition or dosage form in which the agent is releasedaccording to a desired profile in which the release occurs after aperiod of time.

When present in a controlled-release oral dosage form, the compositionsdescribed herein can be administered at a substantially lower dailydosage level than immediate-release forms. At comparable daily dosagelevels, the controlled-release oral solid dosage forms can providegreater in pain relief than immediate-release forms.

Bilayer Tablet

In one embodiment of the invention, the invention relates to multi-layertablets, such as bi-layer tablets. In one embodiment, the bi-layertablet comprises: (a) an immediate-release layer; and (b) acontrolled-release layer. In various embodiments, the immediate-releaselayer or the controlled-released layer comprises one or morepharmaceutically active agents. In one embodiment, a bilayer tablet ofthe invention has a hardness of about 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5,11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 or 15 kiloponds (kp). In oneembodiment, the bilayer tablet has a hardness of about 9.5 kp. In afurther embodiment, a bilayer tablet of the invention has a thickness ofabout 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 mm. It will beunderstood that as to the kilopond and thickness measurements,increments of 0.1 decimal points are within the scope of the invention.A nonlimiting example of a bilayer tablet of the invention is depictedin FIG. 2. In various embodiments, the tablet can be rectangular,tubular, oblong (e.g., FIG. 2), circular, oval or in a capsule form.

In various embodiments, a bilayer tablet of the invention provides aneffective amount of one or more pharmaceutically active agents for about4 to about 6 hours following oral administration, about 12 hoursfollowing oral administration, about 24 hours following oraladministration, or 48 hours following administration. In variousembodiments, the one or more pharmaceutically active agents provided in4-6 hour, 12 hour, 24 hour or 48 hour dosing intervals. Therefore, abilayer tablet of the invention is capable of providing any of the oneor more pharmaceutically active agents disclosed herein in the foregoingdosing intervals.

In one embodiment, a composition comprises promethazine or apharmaceutically acceptable salt thereof and about 70 to about 80% ofthe promethazine or pharmaceutically acceptable salt thereof dissolvesin the stomach of a subject after about 5 to about 10 minutes followingoral administration. In one embodiment, the promethazine is promethazineHCl.

In one embodiment, a composition comprises hydrocodone or apharmaceutically acceptable salt thereof and about 30 to about 60% ofthe hydrocodone or pharmaceutically acceptable salt thereof dissolves inthe stomach of a subject after about 5 to about 10 minutes followingoral administration.

In one embodiment, the hydrocodone salt is hydrocodone bitartrate. Inone embodiment, a composition comprises acetaminophen or apharmaceutically acceptable salt thereof and 50% to about 70% of theacetaminophen or pharmaceutically acceptable salt thereof dissolves inthe stomach of a subject after about 5 to about 10 minutes followingoral administration.

In one embodiment, the composition comprises promethazine or apharmaceutically acceptable salt thereof, hydrocodone or apharmaceutically acceptable salt thereof and acetaminophen or apharmaceutically acceptable salt thereof, and at least 90% of thepharmaceutically active agents in the composition dissolve in thestomach of a subject after about 45 minutes following oraladministration. In one embodiment, the composition is a bilayer tabletcomprising an immediate-release layer and a controlled-release layer.

In one embodiment, the immediate release layer comprises promethazine ora pharmaceutically acceptable salt as the only pharmaceutically activeagent. In another embodiment, the controlled-release layer compriseshydrocodone or a pharmaceutically acceptable salt and acetaminophen or apharmaceutically acceptable salt as the only pharmaceutical ingredients.

In yet another embodiment, the controlled release layer comprises anopioid analgesic or a non-opioid analgesic as the only pharmaceuticallyactive agent. In another embodiment, the controlled release layercomprises an opioid analgesic and a non-opioid analgesic as the onlypharmaceutically active agents. In another embodiment the immediaterelease layer comprises an antiemetic or a stimulant as the onlypharmaceutically active agent. In another embodiment the immediaterelease layer comprises an antiemetic and a stimulant as the onlypharmaceutically active agents.

Immediate-Release Layer

In one embodiment, the immediate-release layer is capable of releasingabout 70 to about 80% of the one or more pharmaceutically active agentcontained therein in the stomach of a subject in about 5 to about 10minutes following oral administration. In one embodiment, theimmediate-release layer is capable of releasing about 90 to about 100%of one or more pharmaceutically active agent contained therein in thestomach of a subject in about 40 minutes.

In one embodiment, the one or more pharmaceutically active agent in theimmediate-release layer is an antiemetic. In one embodiment, theantiemetic is promethazine or a pharmaceutically acceptable saltthereof. In another embodiment, the antiemetic is promethazine HCl.

In one embodiment, an immediate-release layer comprises two or moreagents, including an anti-emetic and a stimulant.

In some embodiments, the immediate-release layer comprises one or moreexcipients, including but not limited to silicified microcrystallinecellulose (e.g., HD90), croscarmellose sodium (AC-Di-Sol), magnesiumstearate. In one embodiment, the total layer weight of theimmediate-release layer is from about 100 to about 300 mg, such as about110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about260 mg, about 270 mg, about 280 mg, about 290 mg, or about 300 mg.

In one embodiment, the immediate-release layer comprises from about 75mg to about 150 mg of silicified microcrystalline cellulose, from about10 mg to about 20 mg croscarmellose sodium, from about 0.5 mg to 2 mgmagnesium stearate. In yet a further embodiment, the immediate-releaselayer comprises from about 10 to about 15 mg promethazine, or apharmaceutically acceptable salt thereof. In another embodiment, theimmediate-release layer comprises about 12.5 mg promethazine or apharmaceutically acceptable salt thereof. In another embodiment, thepharmaceutically acceptable salt is promethazine HCl.

In one embodiment, the immediate-release layer comprise about 12.5 mgpromethazine HCl, about 121.5 mg silicified microcrystalline cellulose,about 15 mg croscarmellose sodium, and about 1 mg magnesium stearate.

In one embodiment, a composition comprising an effective amount of eachof hydrocodone bitartrate, acetaminophen and promethazine HCl is capableof dissolving in the stomach of a subject so that an effective plasmaconcentration of each of pharmaceutically active ingredient is presentin a subject in from about 5 minutes to about 30 minutes.

Controlled-Release Layer

In one embodiment, the controlled-release layer is capable of releasingabout 30 to about 40% of the one or more pharmaceutically active agentcontained therein in the stomach of a subject in about 5 to about 10minutes following oral administration. In another embodiment, thecontrolled-release layer is capable of releasing about 90% of the one ormore pharmaceutically active agents are released in about 40 minutesafter oral administration.

In some embodiment, the controlled-release layer comprises one or moreexcipients, including but not limited to silicified microcrystallinecellulose (e.g., HD90), croscarmellose sodium (AC-Di-Sol), magnesiumstearate. In one embodiment, the total layer weight of thecontrolled-release layer is from about 100 to about 300 mg, such asabout 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg,about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg,about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg,about 260 mg, about 270 mg, about 280 mg, about 290 mg, or about 300 mg.

In one embodiment, a controlled-release layer comprises from about 75 mgto about 250 mg of silicified microcrystalline cellulose, from about 10mg to about 40 mg hydroxyl methyl propyl cellulose, from about 0.5 mg to5 mg magnesium stearate, and from about 0.5 mg to about 5 mg stearicacid.

In one embodiment, the controlled-release layer comprises about 152 mgsilicified microcrystalline cellulose, about 20 mg hydroxyl methylpropyl cellulose, about 2.75 mg magnesium stearate, about 2.75 stearicacid, about 7.5 mg hydrocodone, or a pharmaceutically acceptable saltthereof and about 325 mg acetaminophen or a pharmaceutically acceptablesalt thereof. In yet a further embodiment, the controlled-release layercomprises from about 5 mg to about 12.5 mg hydrocodone or apharmaceutically acceptable salt thereof. In one embodiment, thecontrolled-release layer comprises about 7.5 mg hydrocodone or apharmaceutically acceptable salt thereof. In another embodiment, theopioid analgesic is oxycodone or a pharmaceutically acceptable saltthereof. In one embodiment, the pharmaceutically acceptable salt isoxycodone HCl. In another embodiment, the pharmaceutically acceptablesalt for hydrocodone is hydrocodone bitartrate.

In yet a further embodiment, the controlled-release layer furthercomprises from about 290 mg to about 360 mg acetaminophen or apharmaceutically acceptable salt thereof. In one embodiment thecontrolled-release layer comprises about 325 mg acetaminophen or apharmaceutically acceptable salt thereof.

In one embodiment, the immediate-release layer comprises promethazineHCl and the controlled-release layer comprises hydrocodone bitartrate.In another embodiment, the controlled-release layer further comprises anon-opioid analgesic (e.g., acetaminophen).

In one embodiment, the one or more pharmaceutically active agents of thecontrolled-release layer is an opioid analgesic. In one embodiment, theopioid analgesic is hydrocodone or oxycodone; or a pharmaceuticallyacceptable salt thereof. In one embodiment, the immediate-release layeris about 150 mg in total layer weight and the controlled-release layeris about 550 mg total weight.

Furthermore, in one embodiment, the controlled-release layer comprisesabout 325 mg acetaminophen, about 7.5 mg hydrocodone bitartrate, about152 mg silicified microcrystalline cellulose, about 20 mg hydroxylmethyl propyl cellulose (HPMC), about 2.75 mg magnesium stearate, andabout 2.75 mg stearic acid; and the immediate-release layer comprisesabout 12.5 mg promethazine HCl, about 121 mg silicified microcrystallinecellulose, about 15 mg croscarmellose sodium, and about 1 mg magnesiumstearate.

In various embodiments, a bilayer tablet of the invention can comprisethe combinations of pharmaceutically active agents in Table 1 or Table2, wherein the controlled-release layer comprises one or more opioidanalgesic agents, triptan agents, non-analgesic agents, barbiturates orstimulants, and the immediate-release layer comprises one or morestimulants.

In one embodiment, a stimulant is present in the immediate-releaselayer, controlled-release layer or both layers; the immediate-releaselayer comprises one or more antiemetic or antihistamines; and thecontrolled-release layer comprises one or more non-opioid analgesics. Inaddition, either layer of the bilayered tablet can comprise one or moreanti-abuse agents disclosed herein.

In one embodiment, a bilayer tablet of the invention comprises acontrolled-release layer comprising one or more analgesic agents as theonly pharmaceutically active agents in the controlled-release layer. Inanother embodiment, a bilayer tablet of the invention comprises animmediate-release layer comprising an antiemetic agent as the onlypharmaceutically active agent in the immediate-release layer.

In another embodiment the controlled release layer further comprises oneor more of: silicified microcrystalline cellulose, hydroxy methyl propylcellulose, magnesium stearate, and stearic acid. In another embodimentthe immediate-release layer further comprises one or more of: silicifiedmicrocrystalline cellulose, croscarmellose sodium and magnesiumstearate. In another embodiment the tablet has a hardness of about 9.5kilopond and thickness from about 6.9 to about 7.0 mm. In anotherembodiment the hydrocodone salt is hydrocodone bitartrate. In anotherembodiment the promethazine salt is promethazine HCL. In anotherembodiment the controlled release layer is an inner layer and whereinthe immediate-release layer is an outer layer.

In one embodiment the opioid analgesic is oxycodone or pharmaceuticallyacceptable salt thereof; and the one or more antiemetic is promethazineor a pharmaceutically acceptable salt thereof. In another embodiment theeffective amount is an amount effective for treating or preventing painfor a period of about 12 hours immediately following administration to asubject. In another embodiment the bi-layer tablet comprises animmediate release layer and a controlled release layer. In anotherembodiment the immediate release layer comprises the promethazine orpharmaceutically acceptable salt thereof, and wherein the controlledrelease layer comprises the oxycodone, or a pharmaceutically acceptablesalt thereof. In another embodiment about 70% of the promethazine orpharmaceutically acceptable salt thereof is capable of dissolving in aliquid solution in about 5 minutes after contact with the solution, andwherein about 30% of the oxycodone or pharmaceutically acceptable saltis capable of dissolving in a liquid solution in about 10 minutes aftercontact with the solution. In another embodiment the controlled releaselayer further comprises an antiemetic agent.

In one embodiment the effective amount of the hydrocodone orpharmaceutically acceptable salt thereof is an amount effective fortreating or preventing pain for a period of about 12 hours immediatelyfollowing administration to a subject. In another embodiment thecontrolled release layer comprises about 7.5 mg of hydrocodone or apharmaceutically acceptable salt thereof, about 325 mg of acetaminophenor a pharmaceutically acceptable salt thereof, about 152 mg ofsilicified microcrystalline cellulose, about 20 mg of hydroxy methylpropyl cellulose, about 2.7 mg of magnesium stearate, and about 2.7 mgof stearic acid; and the immediate release layer comprises about 12.5 mgof promethazine or a pharmaceutically acceptable salt thereof, about121.5 mg of silicified microcrystalline cellulose, about 15 mg ofcroscarmellose sodium and about 1 mg of magnesium stearate.

In another embodiment the composition further comprises an effectiveamount of naltrexone or a pharmaceutically acceptable salt thereof. Inanother embodiment the composition is in the form of a bi-layer tablet.In another embodiment the effective amount of the morphine orpharmaceutically acceptable salt thereof is an amount effective fortreating or preventing pain for a period of about 12 hours immediatelyfollowing administration to a subject.

In one embodiment the controlled release layer comprises about 7.5 mg ofhydrocodone or a pharmaceutically acceptable salt thereof, and about 325mg of acetaminophen or a pharmaceutically acceptable salt thereof; andfurther wherein the immediate-release layer comprises about 12 mg ofpromethazine or a pharmaceutically acceptable salt thereof.

In one embodiment the effective amount is an amount effective fortreating or preventing pain for a period of about 12 hours immediatelyfollowing administration to a subject.

In one embodiment the effective amount of the oxycodone orpharmaceutically acceptable salt thereof is an amount effective fortreating or preventing pain for a period of about 12 hours immediatelyfollowing administration to a subject.

Combination Formulations

Various embodiments of the invention are directed to compositionscomprising an effective amount of each of an analgesic and an activeagent that is useful for reducing an adverse effect associated with suchone or more opioid analgesics, or one or more non-opioid analgesic.Various embodiments for compositions of the invention are provided inTable 1 or Table 2.

Such additional active agents include antiemetics and antihistamines. Insome embodiments, the analgesics are opioid or non-opioid analgesics(e.g., hydrocodone or oxycodone, or a pharmaceutically acceptable saltthereof and acetaminophen or a pharmaceutically acceptable saltthereof). In a further embodiment, the active agent which reducesadverse effects of such analgesics is promethazine or a pharmaceuticallyacceptable salt thereof.

In one embodiment, a composition of the invention allows for higherdosages for said analgesics in the composition, by reducing adverseeffects associated with an opioid or non-opioid analgesic. For example,in a subject who could not otherwise tolerate a particular dosage of anopioid analgesic, it is believed that a composition of the inventioncomprising an effective amount of each of an opioid analgesic, anon-opioid analgesic and promethazine or a pharmaceutically acceptablesalt thereof, will reduce an adverse effects (e.g. nausea or vomiting)associated with an opioid analgesic, thus allowing for increased dosagesto be administered. Furthermore, administration can be through a singlecomposition.

In various embodiments, the analgesic agent of the composition is anopioid analgesic agent such as hydrocodone, oxycodone,acetyldihydrocodeinone, diamorphine, codeine, pethidine, alfentanil,buprenorphine, butorphanol, codeine, dezocine, fentanyl, hydromorphone,levomethadyl acetate, levorphanol, meperidine, methadone, morphinesulfate, nalbuphine, oxymorphone, pentazocine, propoxyphene,remifentanil, sufentanil, tramadol, or a pharmaceutically acceptablesalt thereof. In one embodiment, the opioid analgesic agent ishydrocodone, oxycodone, propoxyphene, or fentanyl or a pharmaceuticallyacceptable salt thereof.

In another embodiment, a dosage form comprises an opioid analgesic andone or more antiemetic. In another embodiment, a dosage form compriseshydrocodone or oxycodone or a pharmaceutically acceptable salt thereofand one or more antiemetic, which are disclosed herein.

In some embodiments, a composition of the invention comprises an opioidantagonist agent or abuse deterrent agent such as nalmefene, naloxone,niacin, naltrexone or a pharmaceutically acceptable salt thereof. Thecomposition can further comprise an antitussive such as codeine ordextromethorphan, dextrorphan, or a pharmaceutically acceptable saltthereof.

As stated above, a pharmaceutically active agent can be in the form of apharmaceutically acceptable salt. Each agent disclosed herein can beused in a composition of the invention as its free base or itspharmaceutically acceptable salt, prodrug, analog and complex. Invarious embodiments of the invention, with respect to a pharmaceuticallyactive agent in a composition, a pharmaceutically acceptable saltincludes, but is not limited to, metal salts, such as sodium salts,potassium salts, and lithium salts; alkaline earth metals, such ascalcium salts, magnesium salts, and the like; organic amine salts, suchas triethylamine salts, pyridine salts, picoline salts, ethanolaminesalts, triethanolamine salts, dicyclohexylamine salts,N,N′-dibenzylethylenediamine salts, and the like; inorganic acid saltssuch as hydrochloride salts, hydrobromide salts, sulfate salts,phosphate salts, and the like; organic acid salts such as formate salts,acetate salts, trifluoroacetate salts, maleate salts, tartrate salts,and the like; sulfonate salts such as methanesulfonate salts,benzenesulfonate salts, p-toluenesulfonate salts, and the like; andamino acid salts, such as arginate salts, asparaginate salts, glutamatesalts, and the like.

In addition, pharmaceutically acceptable salts include bitartrate,bitartrate hydrate, hydrochloride, p-toluenesulfonate, phosphate,sulfate, trifluoroacetate, bitartrate hemipentahydrate,pentafluoropropionate, hydrobromide, mucate, oleate, phosphate dibasic,phosphate monobasic, acetate trihydrate, bis(heptafuorobutyrate),bis(pentafluoropropionate), bis(pyridine carboxylate),bis(trifluoroacetate), chlorhydrate, and sulfate pentahydrate. In oneembodiment the agent is hydrocodone, a pharmaceutically acceptable saltor its thiosemicarbazone, p-nitrophenylhydrazone, o-methyloxime,semicarbazone, or bis (methylcarbamate). In another embodiment the agentis oxycodone, a pharmaceutically acceptable salt or itsthiosemicarbazone, p-nitrophenylhydrazone, o-methyloxime, semicarbazone,or bis (methylcarbamate). In a further embodiment the agent isacetaminophen, a pharmaceutically acceptable salt or itsthiosemicarbazone, p-nitrophenylhydrazone, o-methyloxime, semicarbazone,or bis (methylcarbamate). In another embodiment an agent ispromethazine, a pharmaceutically acceptable salt or itsthiosemicarbazone, p-nitrophenylhydrazone, o-methyloxime, semicarbazone,or bis (methylcarbamate). Other representative pharmaceuticallyacceptable salts include, e.g., water-soluble and water-insoluble salts,such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,butyrate, calcium edetate, camphorsulfonate, camsylate, carbonate,citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate,esylate, fiunarate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts. Ahydrate is another example of a pharmaceutically acceptable salt.

In some embodiments, a composition of the invention comprises aneffective amount of each of an opioid analgesic agent and a non-opioidanalgesic agent, where the opioid analgesic agent/non-opioid analgesicagent is codeine/acetaminophen, codeine/aspirin, codeine/naproxen,codeine/ibuprofen, hydrocodone/acetaminophen, hydrocodone/ibuprofen,hydrocodone/naproxen, hydrocodone/aspirin, oxycodone/acetaminophen,oxycodone/aspirin, oxycodone/naproxen, oxycodone/ibuprofen,propoxyphene/aspirin, propoxyphene/ibuprofen,propoxyphene/acetaminophen, or propoxyphene/naproxen, wherein the opioidanalgesic agent or non-opioid analgesic agent is optionally in the formof a or a pharmaceutically acceptable salt thereof. In one embodiment,the hydrocodone salt is hydrocodone bitartrate, the oxycodone salt isoxycodone HCl, and the naproxen salt is naproxen Na or Mg.

In some embodiments the compositions disclosed herein may furthercomprise one or more of an opioid antagonist agent, abuse deterrentagent, a barbiturate agent, a stimulant agent, or an antiemetic agent.

Therefore, in some embodiments, a composition comprises an effectiveamount of an opioid analgesic agent (such as hydrocodone or oxycodone ora pharmaceutically acceptable salt thereof), a non-opioid analgesicagent (such as acetaminophen or naproxen or a pharmaceuticallyacceptable salt thereof) and an active agent useful for reducing oreliminating adverse effects, such as an antihistamine (e.g.,promethazine or a pharmaceutically acceptable salt thereof) or anantiemetic, as described herein. In one embodiment the composition is inthe form of a bi-layer tablet that comprises an immediate-release layerand a controlled-release layer. In a further embodiment theimmediate-release layer comprises one or more of an opioid agent, anon-opioid analgesic agent and an active agent useful for reducing oreliminating adverse effects. In a further embodiment acontrolled-release layer comprises an effective amount of one or more ofan opioid agent, a non-opioid analgesic agent and an active agent usefulfor reducing or eliminating adverse effects associated withadministration of an opioid analgesic agent or non-opioid analgesicagent. In some embodiments a composition further comprises an effectiveamount of an opioid antagonist agent or abuse deterrent agent. In aspecific embodiment the composition comprises hydrocodone or oxycodone,or a pharmaceutically acceptable salt thereof, acetaminophen or apharmaceutically acceptable salt thereof, or naproxen or apharmaceutically acceptable salt thereof, and promethazine or apharmaceutically acceptable salt thereof.

Examples of non-opioid analgesic agents useful in the compositions ofthe invention include but are not limited to acetaminophen; anon-steroidal anti-inflammatory drug (NSAID) such as a salicylate(including, for example, amoxiprin, benorilate, choline magnesiumsalicylate, diflunisal, faislamine, methyl salicylate, magnesiumsalicylate), an arylalkanoic acid (including, for example, diclofenac,aceclofenac, acemetacin, bromfenac, etodolac, indometacin, nabumetone,sulindac, tolmetin), a profen (including, for example, ibuprofen,carprofen, fenbuprofen, flubiprofen, ketaprofen, ketorolac, loxoprofen,naproxen, suprofen), a fenamic acid (including, for example mefenamicacid, meclofenamic acid), an oxicam (including, for example, piroxicam,lomoxicam, meloxicam, tenoxicam), a pyrazolidine derivative (including,for example, phenylbutazone, azapropazone, metamizole, oxyphenbutazone,sulfinprazone) or a pharmaceutically acceptable salt thereof; a Cox-2inhibitor (such as valdecoxib, celecoxib, rofecoxib or apharmaceutically acceptable salt thereof), a local analgesic (such aslidocaine, mexiletine or a pharmaceutically acceptable salt thereof); ananti-depressant (such as amitriptyline, carbamazepine, gabapentin,pregabalin, amoxapine, clomipramine, desipramine, dosulepin, doxepin,imipramine, iprindole, lofepramine, nortriptyline, opipramol,protryptyline, trimipramine or a pharmaceutically acceptable saltthereof) an atypical analgesic (such as orphenadrine, cyclobenzaprine,scopolamine, atropine, gabapentin or a pharmaceutically acceptable saltthereof), a psychotropic agent (such as tetrahydrocannabinol or apharmaceutically acceptable salt thereof), an NMDA receptor antagonist(such as ketamine, amantadine, dextromethorphan, dextrorphan, ibogaine,phencyclidine, riluzole, tiletamine, memantine, dizocilpine, patiganel,remacimide, or a pharmaceutically acceptable salt thereof), anα₂-adrenoreceptor agonists (such as clonidine or a pharmaceuticallyacceptable salt thereof) and a synthetic drug having narcotic propertiessuch as tramadol. In one embodiment the non-opioid analgesic agent isacetaminophen, naproxen or a pharmaceutically acceptable salt thereof.

The agent useful for preventing or alleviating an adverse effectassociated with administration of an opioid analgesic or a non-opioidanalgesic, a triptan, barbiturate or morphine narcotic, includes, forexample, an antihistamine including a histamine agonist and anantagonist which is classified according to receptor subtype.

Such antihistamines include H1 agonists and H1 antagonists. H1 agonistsor partial agonists include 2-(m-fluorophenyl)-histamine and H1antagonists include chlorpheniramine, scopolamine, mepyramine,terfenadine, astemizole, and triprolidine. Further antagonists (whichmay be further classified by their chemical structures) include theethanolamines carbinoxamine, dimenhydrinate, diphenhydramine, anddoxylamine; the ethylaminediamines pyrilamine and tripelennamine; thepiperazine derivatives dydroxyzine, cyclizine, fexofenadine andmeclizine; the alkylamines brompheniramine and chlorpheniramine; andmiscellaneous antagonists cyproheptadine, loratadine, cetrizine. H2agonists include dimaprit, impromidine, and amthamine; and H2antagonists (useful in the treatment of gastric acid secretion) includecimetidine, ranitidine, nizatidine, and famotidine; H3 agonists includeR-alpha-methylhistamine, imetit, and immepip and H3 antagonists includethioperamide, iodophenpropit, and clobenpropit; and H4 agonists includeclobenpropit, imetit, and clozapine and H4 antagonists includethioperamide.

The agent useful for preventing or suppressing a adverse effect can alsoinclude an H1 blocker, such as azelastine, brompheniramine, buclizine,carbinoxamine, cetrizine, chlorpheniramine, clemastine, cyclizine,cyproheptadine, desloratidine, dimenhydrinate, diphenhydramine,emedastine, fexofenadine, hydroxyzine, ketotifen, levocabastine,loratadine, meclizine, olopatadine, phenindamine, and promoathazine.

In various embodiments compositions comprise two, three, four, five, sixor more active agents. In one embodiment at least one of the activeagents is an antiemetic or antihistamine. In other embodiment, acomposition does not comprise promethazine or a pharmaceuticallyacceptable salt. As indicated herein, a composition can comprisepharmaceutically active agents in the combinations provided in Table 1or Table 2.

As indicated above, compositions can comprise an antiemetic agentincluding, for example, aprepitant, dronabinol, perphenazine,palonosetron, trimethyobenzamide, metoclopromide, domperidone,prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine,alizapride, azasetron, benzquinamide, bietanautine, bromopride,buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol,dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl,pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, droperidol, haloperidol,prochloperazine, metoclopramide, diphenhydramine, cannabis, midazolam,lorazepam, hyoscine, dexamethasone, emetrol, propofol and apharmaceutically acceptable salt or mixtures thereof.

In another embodiment the composition can comprise an antitussive agentincluding, for example, dextromethorphan, dextrorphan, noscapine, ethylmorphine, codeine, camphor, menthol, theobromine, guaifenesin, or thelike.

In various embodiments of the invention, a composition comprises atleast two analgesics; and one or more additional pharmaceutically activeagents disclosed in Table 1 or Table 2. In one embodiment, thecomposition further comprises one antihistamine or antiemetic.

In some embodiments a composition comprises a stimulant agent. Stimulantagents useful in the methods and compositions of the invention include,but are not limited to, aminophylline, caffeine, dyphlline,oxitriphylline, theophhylline, amphetamine, benzphetamine,dextroamphetamine, diethylpropion, mazindol, methamphetamine,methylphenidate, dexmethylphenidate, pemoline, sibutramine, modafinil,atomoxetine, phendimetrizine, phenteramine, adrafinil,phenylpropanolamine, psuedoephedrine, synephrine, amphetaminil,furfenorex, or a combination thereof. In some embodiments, compositionscomprise a stimulant agent that provides an anti-sedative effect.

A stimulant agent can be an amphetamine, examples of which include butare not limited to methamphetamine, levoamphetamine, dextroamphetamine,3,5-methyloxy amphetamine, 2,5-dimethoxy-4-methylthioamphetamine,2,5-dimethoxy-4-ethylthioamphetamine,2,5-dimethoxy-4-(i)-propylthioamphetamine,2,5-dimethoxy-4-phenylthioamphetamine,2,5-dimethoxy-4-(n)-propylthioamphetamine, Brolamfetamine,2,5-dimethoxy-4-iodoamphetamine, 2,5-Dimethoxy-4-methylamphetamine,2,5-Dimethoxy-4-butyl-amphetamine,3,4-Dimethyl-2,5-dimethoxyamphetamine, 2-Phenylethylamine,propylamphetamine, methylphenidate, lisdexamfetamine, ethylamphetamine,MDMA (3,4-methylenedioxy-N-methylamphetamine), MDEA(3,4-methylenedioxy-N-ethylamphetamine), PMA (p-methoxyamphetamine), DMA(2-(2,4-Dimethoxy-phenyl)-1-methyl-ethylamine), benzphetamine, 4-FMP(para-fluoroamphetamine), or 4-MTA (4-Methylthioamphetamine), or apharmaceutically acceptable salt thereof.

In one embodiment, a composition is provided that comprises an effectiveamount of an opioid (such as hydrocodone, propoxyphene, fentanyl oroxycodone, or a pharmaceutically acceptable salt thereof) and astimulant (such as modafinil or caffeine, or a pharmaceuticallyacceptable salt thereof). In some embodiments a composition furthercomprises an antiemetic. In one embodiment, the antiemetic ispromethazine or a pharmaceutically acceptable salt thereof. In yetanother embodiment, the composition further comprises a non-analgesicagent disclosed herein. In one embodiment, the non-opioid analgesic isacetaminophen or a pharmaceutically acceptable salt thereof, or naproxenor a pharmaceutically acceptable salt thereof.

In a further a composition is in the form of a bilayer tablet comprisingan immediate-release layer and a controlled-release layer, wherein theimmediate-release layer comprises and/or the chronic-release layercomprise a stimulant agent. In one embodiment, the controlled-releaselayer comprises an opioid agent. In yet a further embodiment, thecontrolled-release layer further comprises an effective amount of asecond or same stimulant agent as compared to the immediate-releaselayer. In yet another embodiment, the immediate-release layer and/or thecontrolled-release layer further comprises an antiemetic agent. In afurther embodiment the immediate-release layer comprises an effectiveamount of one or more of an opioid agent, a stimulant agent and anantiemetic agent. In another further embodiment a controlled-releaselayer comprises an effective amount of one or more of an opioid agent, astimulant agent, and an antiemetic agent. In some embodiments thecomposition further comprises an effective amount of an opioidantagonist agent or abuse deterrent agent.

In a specific embodiment a composition is provided that compriseshydrocodone or oxycodone, or a pharmaceutically acceptable salt thereof,modafinil or caffeine or a pharmaceutically acceptable salt thereof andoptionally promethazine or a pharmaceutically acceptable salt thereof.

In some embodiments compositions comprise a barbiturate active agent.Barbiturate agents useful in the methods and compositions include, butare not limited to, Allobarbital, Alphenal, Amobarbital, Aprobarbital,Barbexaclone, Barbital, Brallobarbital, Butabarbital, Butalbital,Butobarbital, Butallylonal, Crotylbarbital, Cyclobarbital, Cyclopal,Ethallobarbital, Febarbamate, Heptabarbital, Hexethal, Hexobarbital,Mephobarbital, Metharbital, Methohexital, Methylphenobarbital,Narcobarbital, Nealbarbital, Pentobarbital, Primidone, Probarbital,Propallylonal, Proxibarbal, Proxibarbital, Reposal, Secbutabarbital,Secobarbital, Sigmodal, Talbutal, Thialbarbital, Thiamylal,Thiobarbital, Thiobutabarbital, Thiopental, Valofane, Vinbarbital,Vinylbital, 1,3-dimethoxymethyl 5,5-diphenyl-barbituric acid (DMMDPB),1-monomethoxymethyl 5,5-diphenylbarbituric acid (MMMDPB), adiphenyl-barbituric acid (DPB) and their precursors, derivatives andanalogs or a combination thereof and a pharmaceutically acceptable saltthereof.

In another embodiment, a composition is provided that comprises aneffective amount of an opioid agent (such as hydrocodone, propoxyphene,fentanyl or oxycodone, or a pharmaceutically acceptable salt thereof); anon-opioid agent (such as acetaminophen or naproxen, or apharmaceutically acceptable salt thereof); a barbiturate agent (such asbutalbital, or a pharmaceutically acceptable salt thereof) andoptionally an antiemetic (such as promethazine, or a pharmaceuticallyacceptable salt thereof).

In a further embodiment a composition is in the form of a bilayertablet, wherein the composition comprises an effective amount of each ofan opioid agent, a non-opioid analgesic agent, a barbiturate agent andan antiemetic agent. In one embodiment the bi-layer tablet comprises animmediate-release layer and a controlled-release layer. In a furtherembodiment the immediate-release layer comprises an effective amount ofone or more of an opioid agent, a non-opioid analgesic agent, abarbiturate agent and an antiemetic agent. In another further embodimenta controlled-release layer comprises an effective amount of one or moreof an opioid agent, a barbiturate agent, a non-opioid analgesic agent,and an antiemetic agent. In some embodiments a composition furthercomprises an effective amount of an opioid antagonist agent or abusedeterrent agent. In a specific embodiment a composition compriseshydrocodone or oxycodone, or a pharmaceutically acceptable salt thereofacetaminophen, or a pharmaceutically acceptable salt thereof, butalbitalor a pharmaceutically acceptable salt thereof and optionallypromethazine or a pharmaceutically acceptable salt thereof.

In another embodiment a composition comprises an effective amount ofeach of an opioid agent (such as hydrocodone, propoxyphene, fentanyl oroxycodone or a pharmaceutically acceptable salt thereof); a barbiturateagent (such as butalbital or a pharmaceutically acceptable saltthereof); a stimulant agent (such as modafinil or caffeine or apharmaceutically acceptable salt thereof); and optionally a non-opioidagent (such as acetaminophen or naproxen or a pharmaceuticallyacceptable salt thereof). In some embodiments the composition furthercomprises an antiemetic (such as promethazine or a pharmaceuticallyacceptable salt thereof).

In one embodiment, such a composition is in the form of a bi-layertablet, wherein the composition comprises an effective amount of anopioid agent, a non-opioid analgesic agent, a barbiturate agent, astimulant agent and optionally an antiemetic agent. In one embodimentthe bi-layer tablet comprises an immediate-release layer and acontrolled-release layer. In a further embodiment the immediate-releaselayer comprises an effective amount of one or more of an opioid agent, anon-opioid analgesic agent, a barbiturate agent, a stimulant agent andan antiemetic agent. In another further embodiment a controlled-releaselayer comprises an effective amount of one or more of an opioid agent, anon-opioid analgesic agent, a barbiturate agent, a stimulant agent andan antiemetic agent. In some embodiments a composition further comprisesan effective amount of an opioid antagonist agent or abuse deterrentagent. In a specific embodiment a composition comprises hydrocodone,propoxyphene or oxycodone, or a pharmaceutically acceptable saltthereof; butalbital, naproxen, caffeine or a pharmaceutically acceptablesalt thereof; and optionally promethazine or a pharmaceuticallyacceptable salt thereof.

In another embodiment a composition comprises an effective amount of anopioid agent (hydrocodone or oxycodone or a pharmaceutically acceptablesalt thereof); and a barbiturate agent (such as butalbital or apharmaceutically acceptable salt thereof). In some embodiments acomposition further comprises an antiemetic (such as promethazine or apharmaceutically acceptable salt thereof). In a further the compositionis in the form of a bi-layer tablet, wherein the composition comprisesan effective amount of each of an opioid analgesic agent, a barbiturateagent, and optionally an antiemetic agent. In one embodiment thebi-layer tablet comprises an immediate-release layer and acontrolled-release layer. In a further embodiment the immediate-releaselayer comprises an effective amount of each of one or more of an opioidanalgesic agent, a barbiturate agent, or an antiemetic agent. In anothera further embodiment a controlled-release layer comprises an effectiveamount of each of one or more of an opioid analgesic agent, abarbiturate agent, or an antiemetic agent. In some the compositionfurther comprises an effective amount of an opioid antagonist agent orabuse deterrent agent. In a specific embodiment a composition comprisesbutalbital, hydrocodone or oxycodone, or a pharmaceutically acceptablesalt thereof and optionally promethazine or a pharmaceuticallyacceptable salt thereof.

In another embodiment a composition comprises an effective amount of anon-opioid agent (such as acetaminophen, naproxen or ibuprofen or apharmaceutically acceptable salt thereof); a barbiturate agent (such asbutalbital or a pharmaceutically acceptable salt thereof); and anantiemetic (such as promethazine or a pharmaceutically acceptable saltthereof). In one embodiment, the composition comprises about 50 mgbutalbital or a pharmaceutically acceptable salt thereof, about 325 mgN-Acetyl-p-Aminophenol or a pharmaceutically acceptable salt thereof,and about 12.5 mg promethazine or a pharmaceutically acceptable saltthereof. In one embodiment, the promethazine salt is promethazine HCl.

In another embodiment a composition comprises an effective amount ofeach of a non-opioid agent (such as acetaminophen, naproxen or ibuprofenor a pharmaceutically acceptable salt thereof); a barbiturate agent(such as butalbital or a pharmaceutically acceptable salt thereof); anda stimulant agent (such as modafinil or caffeine or a pharmaceuticallyacceptable salt thereof). In some embodiments the composition furthercomprises an antiemetic (such as promethazine or a pharmaceuticallyacceptable salt thereof). In a further embodiment an effective amount ofa composition is in the form of a bi-layer tablet, wherein thecomposition comprises an effective amount of each of a non-opioidanalgesic agent, a barbiturate agent, a stimulant agent and optionallyan antiemetic agent. In one embodiment the bi-layer tablet comprises animmediate-release layer and a controlled-release layer. In a furtherembodiment the immediate-release layer comprises an effective amount ofone or more of a non-opioid analgesic agent, a barbiturate agent, astimulant agent or an antiemetic agent. In another a further embodimenta controlled-release layer comprises one or more of a non-opioidanalgesic agent, a barbiturate agent, stimulant agent or an antiemeticagent. In a specific embodiment a composition comprises butalbital,naproxen, caffeine, or a pharmaceutically acceptable salt thereof andoptionally promethazine or a pharmaceutically acceptable salt thereof.

In another embodiment a composition comprises an effective amount of abarbiturate agent (such as butalbital or a pharmaceutically acceptablesalt thereof) and a stimulant agent (such as modafinil or caffeine or apharmaceutically acceptable salt thereof). In some embodiments thecomposition further comprises an antiemetic (such as promethazine or apharmaceutically acceptable salt thereof). In another embodiment, acomposition is in the form of a bi-layer tablet, wherein the compositioncomprises an effective amount of each of a barbiturate agent, astimulant agent and optionally an antiemetic agent. In one embodimentthe bi-layer tablet comprises an immediate-release layer and acontrolled-release layer. In a further embodiment the immediate-releaselayer comprises an effective amount of each of one or more of abarbiturate agent, a stimulant agent or an antiemetic agent. In anothera further embodiment a controlled-release layer comprises an effectiveamount of each of one or more of a barbiturate agent, stimulant agent oran antiemetic agent. In a specific embodiment a composition comprisesbutalbital or a pharmaceutically acceptable salt thereof, caffeine or apharmaceutically acceptable salt thereof and optionally promethazine ora pharmaceutically acceptable salt thereof.

In another embodiment a composition comprises an effective amount of anon-opioid agent (such as ibuprofen or naproxen or a pharmaceuticallyacceptable salt thereof) and a stimulant agent (such as modafinil orcaffeine or a pharmaceutically acceptable salt thereof). In someembodiments the composition further comprises an antiemetic (such aspromethazine or a pharmaceutically acceptable salt thereof). In oneembodiment, the composition is in the form of a bi-layer tablet, whereinthe composition comprises an effective amount of each of a non-opioidagent, a stimulant agent and optionally an antiemetic agent. In oneembodiment the bi-layer tablet comprises an immediate-release layer anda controlled-release layer. In a further embodiment theimmediate-release layer comprises an effective amount of each of one ormore of a non-opioid agent, a stimulant agent or an antiemetic agent. Inanother further embodiment the controlled-release layer comprises aneffective amount of each of one or more of a non-opioid agent, stimulantagent or an antiemetic agent. In a specific embodiment a compositioncomprises naproxen or a pharmaceutically acceptable salt thereof andcaffeine or a pharmaceutically acceptable salt thereof and optionallypromethazine or a pharmaceutically acceptable salt thereof.

The present compositions can comprise one or more beta blockers,serotonin receptor agonists, vasoconstrictors, anti-platelet agents,anti-convulsants, triptans, ergots, or calcitonin-gene-related peptide(CGRP) receptor antagonists.

Non-limiting examples of beta blockers are acebutolol, arotinolol,atenolol, betaxolol, bisoprolol, butoxamine, carvedilol, carteolol,esmolol, carteolol, carvedilol, labetalol, levobunolol, mepindolol,metoprolol, nebivolol, nadolol, oxprenolol, penbutolol, propranolol,pindolol, sotalol, and timolol. In one embodiment, the beta blocker ispropanolol.

Non-limiting examples of serotonin receptor agonists are buspirone,mescaline, psilocybin, cisapride, triptans, or lysergic aciddiethylamide. Non-limiting examples of vasoconstrictors areisometheptene mucate, amphetamines, antihistamines, cocaine, caffeine,pseudoephedrine, ergine, methylphenidate, psilocybin, or stimulants suchas amphakines (e.g., drugs effective to glutagatergic AMPA receptors andbenzoylpiperidine derivatives). Non-limiting examples of amphetaminesand antihistamines are disclosed herein above.

Non-limiting examples of anti-platelet agents are acetylsalycyclic acid,clopidogrel, ticlopidine, cilostazol, abciximab, eptifibatide, tirofibandefibrotide and dipyridamole.

Non-limiting examples of anti-convulsants are topiramate, divaprex,pehnobarbital, methlyphenobarbital, metharbital, barbexaclone,stiripentol, clobazam, clonazepam, clorazepate, diazepam, midazolam,lorazepam, nitrazepam, temazepam, nimetazepam, potassium bromide,felbamate, carbamazepine, oxcarbazepine, vigabatrin, progabide,tiagabine, gabapentin, prgabalin, ethotoin, phenytoin, mephenytoin,fosphenytoin, paramethadione, trimethadione, ethadione, beclaminde,primidone, brivaracetam, levetiracetam, seletracetam, ethsuximide,phesuximide, mesuximide, acetazolamide, sulthiame, methazolamide,zonisamide, lamotrigine, pheneturide, phenacemide, valpromide,valnoctamide and pharmaceutically acceptable salt thereof.

Non-limiting examples of calcitonin-gene-related peptide (CGRP) receptorantagonists are MK-0974, CGRP8-37, BIBN 4096 BS, quinine,nitrobenzamide, 4-oxobutanamides, cyclopropane derivatives, andbenzimidazolinyl piperidines.

Non-limiting examples of triptans are naratriptan, almotriptan,sumatriptan, zolmitriptan, eletriptan, frovatriptan, or rizatriptan, ora pharmaceutically acceptable salt thereof. In some embodiments, a oraldosage form (e.g., bilayer tablet) is provided comprising one or moretriptan and one or more antiemetic. In one embodiment, the triptan issumatriptan or a pharmaceutically acceptable salt thereof, and theantiemetic is promethazine or a pharmaceutically acceptable saltthereof. In a further embodiment, the composition is a bilayer tabletcomprising a controlled-release layer and an immediate-release layer,wherein the controlled-release layer comprises an effective amount ofthe sumatriptan or a pharmaceutically acceptable salt thereof and theimmediate release layer comprises an effective amount of thepromethazine or a pharmaceutically acceptable salt thereof. In oneembodiment, the sumatriptan salt is sumatriptan succinate.

Non-limiting examples of ergots are ergotamine, methysergide, zonisamideand pharmaceutically acceptable salt thereof. In one embodiment, thecompositions comprises: sumatriptan or a pharmaceutically acceptablesalt thereof in a dosage from about 25 mg to about 100 mg andpromethazine or a pharmaceutically acceptable salt thereof in a dosageof from about 12.5 mg to about 50 mg.

In various embodiments, compositions of the invention are administeredin a single dosage form which comprises active agents as disclosed inTable 1 or Table 2 and one or more beta blockers, serotonin receptoragonists, vasoconstrictors, anti-platelet agents, anti-convulsants,triptans, ergot alkaloids, and calcitonin-gene-related peptide (CGRP)receptor antagonists.

In some embodiments, a single dosage form is a multilayered tablet whichcomprises one or more pharmaceutically active agents which includes oneor more beta blockers, serotonin receptor agonists, vasoconstrictors,anti-platelet agents, anti-convulsants, triptans, ergot alkaloids, orcalcitonin-gene-related peptide (CGRP) receptor antagonists. In oneembodiment, a multilayer tablet comprises at least one immediate releaselayer and at least one controlled-released layer. Compositions of theinvention can be administered using other dosage forms disclosed herein.

In yet other embodiments, compositions comprising one or more activeagents disclosed herein (e.g., Table 1 or Table 2) of the invention areadministered prior to, concurrent with, or after administration of oneor more beta blockers, serotonin receptor agonists, vasoconstrictors,anti-platelet agents, anti-convulsants, triptans, ergot alkaloids, orcalcitonin-gene-related peptide (CGRP) receptor antagonists. In someembodiments the present methods for treating or preventing pain furthercomprise administering an effective amount of one or more beta blockers,serotonin receptor agonists, vasoconstrictors, anti-platelet agents,anti-convulsants, triptans, ergots, or CGRP receptor antagonists.

Dosage

In various embodiments compositions of the invention comprise multipleactive agents at the same or different dosages. In some embodiments, theanalgesic components may vary in dosages as further described herein,and the antihistamine or antiemetic dosage can be adjusted according tothe particular analgesics used.

For example, in various embodiments compositions are provided thatcomprise an opioid analgesic agent that is present at from about a doseof about 1.0 mg to about 100 mg, including but not limited to 1.0 mg,1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg,8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30mg, 30.5 mg, 31 mg, 31.5 mg, 32 mg, 32.5 mg, 33 mg, 33.5 mg, 36 mg, 36.5mg, 37 mg, 37.5 mg, 38 mg, 38.5 mg, 39 mg, 39.5 mg, 40 mg, 40.5 mg, 41mg, 41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 mg, 44 mg, 44.5 mg, 45 mg, 45.5mg, 46 mg, 46.5 mg, 47 mg, 47.5 mg, 48 mg, 48.5 mg, 49 mg, 49.5 mg, 50mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or100 mg. In one embodiment the opioid analgesic agent is hydrocodone oroxycodone or salt thereof. In another embodiment the opioid analgesicagent is present in a bi-layer tablet that comprises an immediaterelease and a controlled release layer.

In another embodiment a composition is provided that comprises anon-opioid analgesic that is present at a dose from about 200 mg toabout 1000 mg, including but not limited to 200 mg, 205 mg, 210 mg, 215mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305mg, 310 mg, 315 mg, 320 mg, 325 mg, 326 mg, 326.5 mg, 327 mg, 327.5 mg,328 mg, 328.5 mg, 329 mg, 329.5 mg, 330 mg, 330.5 mg, 331 mg, 331.5 mg,332 mg, 332.5 mg, 333 mg, 333.5 mg, 334 mg, 334.5 mg, 335 mg, 335.5 mg,336 mg, 336.5 mg, 337 mg, 337.5 mg, 338 mg, 338.5 mg, 339 mg, 339.5 mg,340 mg, 340.5 mg, 341 mg, 341.5 mg, 342 mg, 342.5 mg, 343 mg, 343.5 mg,344 mg, 344.5 mg, 345 mg, 345.5 mg, 346 mg, 346.5 mg, 347 mg, 347.5 mg,348 mg, 348.5 mg, 349 mg, 349.5 mg, 350 mg, 350.5 mg, 351 mg, 351.5 mg,352 mg, 352.5 mg, 353 mg, 353.5 mg, 354 mg, 354.5 mg, 355 mg, 355.5 mg,356 mg, 356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, 359.5 mg,360 mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, 362.5 mg, 363 mg, 363.5 mg,364 mg, 364.5 mg, 365 mg, 365.5 mg, 366 mg, 366.5 mg, 367 mg, 367.5 mg,368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg, 372.5 mg,373 mg, 373.5 mg, 374 mg, 374.5 mg, 375 mg, 375.5 mg, 376 mg, 376.5 mg,377 mg, 377.5 mg, 378 mg, 378.5 mg, 379 mg, 379.5 mg, 380 mg, 380.5 mg,381 mg, 381.5 mg, 382 mg, 382.5 mg, 383 mg, 383.5 mg, 384 mg, 384.5 mg,385 mg, 385.5 mg, 386 mg, 386.5 mg, 387 mg, 387.5 mg, 388 mg, 388.5 mg,389 mg, 389.5 mg, 390 mg, 390.5 mg, 391 mg, 391.5 mg, 392 mg, 392.5 mg,393 mg, 393.5 mg, 394 mg, 394.5 mg, 395 mg, 395.5 mg, 396 mg, 396.5 mg,397 mg, 397.5 mg, 398 mg, 398.5 mg, 399 mg, 399.5 mg, 400 mg, 405 mg,410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg,455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg,500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg,545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg,590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg,635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 675 mg, 680 mg,685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg,730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg,775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg,820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg,865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg,910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg,955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 995 mg,or 1000 mg. In one embodiment the non-opioid analgesic agent is presentin a bi-layer tablet that comprises an immediate release and acontrolled release layer.

In another embodiment the compositions comprise an antiemetic orantihistamine agent (e.g., promethazine) present at a dose from about0.5 mg to about 200 mg of promethazine or a pharmaceutically acceptablesalt thereof, including but not limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg,15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg,20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg,24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg,29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg,38 mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48mg, 49 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180mg, 185 mg, 190 mg, 195 mg, or 200 mg. In one embodiment the antiemeticor antihistamine agent is present in a bi-layer tablet that comprises animmediate release and a controlled release layer.

In one embodiment, the compositions of the invention comprise an opioidanalgesic agent (such as hydrocodone), a pharmaceutically acceptablesalt or its thiosemicarbazone, p-nitrophenylhydrazone, o-methyloxime,semicarbazone, or bis (methylcarbamate) (each of the foregoing being ahydrocodone agent or derivative); acetaminophen; and promethazine orsalt thereof. Furthermore, the opioid analgesic agent is present in arange of from about 1.0 mg to about 100 mg, including but not limited to1 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 6.5 mg, 7.0 mg,7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg,12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg,16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg,21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg,25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg,30 mg, 30.5 mg, 31 mg, 31.5 mg, 32 mg, 32.5 mg, 33 mg, 33.5 mg, 36 mg,36.5 mg, 37 mg, 37.5 mg, 38 mg, 38.5 mg, 39 mg, 39.5 mg, 40 mg, 40.5 mg,41 mg, 41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 mg, 44 mg, 44.5 mg, 45 mg,45.5 mg, 46 mg, 46.5 mg, 47 mg, 47.5 mg, 48 mg, 48.5 mg, 49 mg, 49.5 mg,50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or100 mg.

Furthermore, in various embodiments, the compositions of the inventioncomprise acetaminophen or a pharmaceutically acceptable salt thereof ispresent in the composition at a range of from about 200 mg to about 1000mg, including but not limited to 200 mg, 205 mg, 210 mg, 215 mg, 220 mg,225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg,270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg,315 mg, 320 mg, 325 mg, 326 mg, 326.5 mg, 327 mg, 327.5 mg, 328 mg,328.5 mg, 329 mg, 329.5 mg, 330 mg, 330.5 mg, 331 mg, 331.5 mg, 332 mg,332.5 mg, 333 mg, 333.5 mg, 334 mg, 334.5 mg, 335 mg, 335.5 mg, 336 mg,336.5 mg, 337 mg, 337.5 mg, 338 mg, 338.5 mg, 339 mg, 339.5 mg, 340 mg,340.5 mg, 341 mg, 341.5 mg, 342 mg, 342.5 mg, 343 mg, 343.5 mg, 344 mg,344.5 mg, 345 mg, 345.5 mg, 346 mg, 346.5 mg, 347 mg, 347.5 mg, 348 mg,348.5 mg, 349 mg, 349.5 mg, 350 mg, 350.5 mg, 351 mg, 351.5 mg, 352 mg,352.5 mg, 353 mg, 353.5 mg, 354 mg, 354.5 mg, 355 mg, 355.5 mg, 356 mg,356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, 359.5 mg, 360 mg,360.5 mg, 361 mg, 361.5 mg, 362 mg, 362.5 mg, 363 mg, 363.5 mg, 364 mg,364.5 mg, 365 mg, 365.5 mg, 366 mg, 366.5 mg, 367 mg, 367.5 mg, 368 mg,369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg, 372.5 mg, 373 mg,373.5 mg, 374 mg, 374.5 mg, 375 mg, 375.5 mg, 376 mg, 376.5 mg, 377 mg,377.5 mg, 378 mg, 378.5 mg, 379 mg, 379.5 mg, 380 mg, 380.5 mg, 381 mg,381.5 mg, 382 mg, 382.5 mg, 383 mg, 383.5 mg, 384 mg, 384.5 mg, 385 mg,385.5 mg, 386 mg, 386.5 mg, 387 mg, 387.5 mg, 388 mg, 388.5 mg, 389 mg,389.5 mg, 390 mg, 390.5 mg, 391 mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg,393.5 mg, 394 mg, 394.5 mg, 395 mg, 395.5 mg, 396 mg, 396.5 mg, 397 mg,397.5 mg, 398 mg, 398.5 mg, 399 mg, 399.5 mg, 400 mg, 405 mg, 410 mg,415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg,460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg,505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg,550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg,595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg,640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 675 mg, 680 mg, 685 mg,690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg,735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg,780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg, 820 mg,825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg,870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg,915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg, 955 mg,960 mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 995 mg, or 1000mg. In addition, the promethazine or salt thereof is present in thecomposition at a dose between about 0.5 mg to about 200 mg, includingbut not limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg,12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg,17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg,21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg,26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg,31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41mg, 12 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195mg, or 200 mg. In one embodiment hydrocodone or a salt thereof,acetaminophen or a salt thereof, and promethazine or a salt thereof arepresent in a bi-layer tablet that comprises an immediate release and acontrolled release layer. In another embodiment the immediate releaselayer comprises promethazine or a salt thereof and the controlledrelease layer comprises hydrocodone or a salt thereof and acetaminophenor a salt thereof.

In various embodiments, the compositions of the invention comprise anopioid analgesic agent (such as hydrocodone or oxycodone or apharmaceutically acceptable salt thereof), acetaminophen or apharmaceutically acceptable salt thereof and promethazine or apharmaceutically acceptable salt thereof, wherein the compositioncomprises the respective agents, opioid analgesic agent: acetaminophenor a salt thereof: promethazine or a pharmaceutically acceptable saltthereof in a ratio by weight of about (1 to 2):(40 to 45):(1 to 2), suchas about 1:40:1, 1:40:1.1, 1:40:1.2, 1:40:1.3, 1:40:1.4, 1:40:1.5,1:40:1.6, 1:40:1.7, 1:40:1.8, 1:40:1.9, 1:40:2, 1.1:40:1, 1.2:40:1,1.3:40:1, 1.4:40:1, 1.5:40:1, 1.6:40:1, 1.7:40:1, 1.8:40:1, 1.9:40:1,2:40:1, 1:41:1, 1:41:1.1, 1:41:1.2, 1:41:1.3, 1:41:1.4, 1:41:1.5,1:41:1.6, 1:41:1.7, 1:41:1.8, 1:41:1.9, 1:41:2, 1.1:41:1, 1.2:41:1,1.3:41:1, 1.4:41:1, 1.5:41:1, 1.6:41:1, 1.7:41:1, 1.8:41:1, 1.9:41:1,2:41:1, 1:42:1, 1:42:1.1, 1:42:1.2, 1:42:1.3, 1:42:1.4, 1:42:1.5,1:42:1.6, 1:42:1.7, 1:42:1.8, 1:42:1.9, 1:42:2, 1.1:42:1, 1.2:42:1,1.3:42:1, 1.4:42:1, 1.5:42:1, 1.6:42:1, 1.7:42:1, 1.8:42:1, 1.9:42:1,2:42:1, 1:43:1, 1:43:1.1, 1:43:1.2, 1:43:1.3, 1:43:1.4, 1:43:1.5,1:43:1.6, 1:43:1.7, 1:43:1.8, 1:43:1.9, 1:43:2, 1.1:43:1, 1.2:43:1,1.3:43:1, 1.4:43:1, 1.5:43:1, 1.6:43:1, 1.7:43:1, 1.8:43:1, 1.9:43:1,2:43:1, 1:43.1:1, 1:43.1:1.1, 1:43.1:1.2, 1:43.1:1.3, 1:43.1:1.4,1:43.1:1.5, 1:43.1:1.6, 1:43.1:1.7, 1:43.1:1.8, 1:43.1:1.9, 1:43.1:2,1.1:43.1:1, 1.2:43.1:1, 1.3:43.1:1, 1.4:43.1:1, 1.5:43.1:1, 1.6:43.1:1,1.7:43.1:1, 1.8:43.1:1, 1.9:43.1:1, 2:43.1:1, 1:43.2:1, 1:43.2:1.1,1:43.2:1.2, 1:43.2:1.3, 1:43.2:1.4, 1:43.2:1.5, 1:43.2:1.6, 1:43.2:1.7,1:43.2:1.8, 1:43.2:1.9, 1:43.2:2, 1.1:43.2:1, 1.2:43.2:1, 1.3:43.2:1,1.4:43.2:1, 1.5:43.2:1, 1.6:43.2:1, 1.7:43.2:1, 1.8:43.2:1, 1.9:43.2:1,2:43.2:1, 1:43.3:1, 1:43.3:1.1, 1:43.3:1.2, 1:43.3:1.3, 1:43.3:1.4,1:43.3:1.5, 1:43.3:1.6, 1:43.3:1.7, 1:43.3:1.8, 1:43.3:1.9, 1:43.3:2,1.1:43.3:1, 1.2:43.3:1, 1.3:43.3:1, 1.4:43.3:1, 1.5:43.3:1, 1.6:43.3:1,1.7:43.3:1, 1.8:43.3:1, 1.9:43.3:1, 2:43.3:1, 1:43.4:1, 1:43.4:1.1,1:43.4:1.2, 1:43.4:1.3, 1:43.4:1.4, 1:43.4:1.5, 1:43.4:1.6, 1:43.4:1.7,1:43.4:1.8, 1:43.4:1.9, 1:43.4:2, 1.1:43.4:1, 1.2:43.4:1, 1.3:43.4:1,1.4:43.4:1, 1.5:43.4:1, 1.6:43.4:1, 1.7:43.4:1, 1.8:43.4:1, 1.9:43.4:1,2:43.4:1, 1:43.5:1, 1:43.5:1.1, 1:43.5:1.2, 1:43.5:1.3, 1:43.5:1.4,1:43.5:1.5, 1:43.5:1.6, 1:43.5:1.7, 1:43.5:1.8, 1:43.5:1.9, 1:43.5:2,1.1:43.5:1, 1.2:43.5:1, 1.3:43.5:1, 1.4:43.5:1, 1.5:43.5:1, 1.6:43.5:1,1.7:43.5:1, 1.8:43.5:1, 1.9:43.5:1, 2:43.5:1, 1:43.6:1, 1:43.6:1.1,1:43.6:1.2, 1:43.6:1.3, 1:43.6:1.4, 1:43.6:1.5, 1:43.6:1.6, 1:43.6:1.7,1:43.6:1.8, 1:43.6:1.9, 1:43.6:2, 1.1:43.6:1, 1.2:43.6:1, 1.3:43.6:1,1.4:43.6:1, 1.5:43.6:1, 1.6:43.6:1, 1.7:43.6:1, 1.8:43.6:1, 1.9:43.6:1,2:43.6:1, 1:43.7:1, 1:43.7:1.1, 1:43.7:1.2, 1:43.7:1.3, 1:43.7:1.4,1:43.7:1.5, 1:43.7:1.6, 1:43.7:1.7, 1:43.7:1.8, 1:43.7:1.9, 1:43.7:2,1.1:43.7:1, 1.2:43.7:1, 1.3:43.7:1, 1.4:43.7:1, 1.5:43.7:1, 1.6:43.7:1,1.7:43.7:1, 1.8:43.7:1, 1.9:43.7:1, 2:43.7:1, 1:43.8:1, 1:43.8:1.1,1:43.8:1.2, 1:43.8:1.3, 1:43.8:1.4, 1:43.8:1.5, 1:43.8:1.6, 1:43.8:1.7,1:43.8:1.8, 1:43.8:1.9, 1:43.8:2, 1.1:43.8:1, 1.2:43.8:1, 1.3:43.8:1,1.4:43.8:1, 1.5:43.8:1, 1.6:43.8:1, 1.7:43.8:1, 1.8:43.8:1, 1.9:43.8:1,2:43.8:1, 1:43.9:1, 1:43.9:1.1, 1:43.9:1.2, 1:43.9:1.3, 1:43.9:1.4,1:43.9:1.5, 1:43.9:1.6, 1:43.9:1.7, 1:43.9:1.8, 1:43.9:1.9, 1:43.9:2,1.1:43.9:1, 1.2:43.9:1, 1.3:43.9:1, 1.4:43.9:1, 1.5:43.9:1, 1.6:43.9:1,1.7:43.9:1, 1.8:43.9:1, 1.9:43.9:1, 2:43.9:1, 1:44:1, 1:44:1.1,1:44:1.2, 1:44:1.3, 1:44:1.4, 1:44:1.5, 1:44:1.6, 1:44:1.7, 1:44:1.8,1:44:1.9, 1:44:2, 1.1:44:1, 1.2:44:1, 1.3:44:1, 1.4:44:1, 1.5:44:1,1.6:44:1, 1.7:44:1, 1.8:44:1, 1.9:44:1, 2:44:1, 1:45:1, 1:45:1.1,1:45:1.2, 1:45:1.3, 1:45:1.4, 1:45:1.5, 1:45:1.6, 1:45:1.7, 1:45:1.8,1:45:1.9, 1:45:2, 1.1:45:1, 1.2:45:1, 1.3:45:1, 1.4:45:1, 1.5:45:1,1.6:45:1, 1.7:45:1, 1.8:45:1, 1.9:45:1, or 2:45:1. For example, in oneembodiment, the ratio of amounts for each active agent is about(1):(43.33):(1.67) for hydrocodone or a salt thereof: acetaminophen or asalt thereof: promethazine or a pharmaceutically acceptable saltthereof, respectively. In one embodiment a pharmaceutically acceptablesalt of hydrocodone, acetaminophen orpromethazine is provided. In oneembodiment an opioid analgesic agent (such as hydrocodone or oxycodoneor a salt thereof), acetaminophen or a salt thereof; and promethazine ora salt thereof are present in a bi-layer tablet that comprises animmediate release and a controlled release layer.

In another embodiment, the composition comprises oxycodone, apharmaceutically acceptable salt or its thiosemicarbazone,p-nitrophenylhydrazone, o-methyloxime, semicarbazone, or bis(methylcarbamate) (each of the foregoing being a hydrocodone agent orderivative); acetaminophen or a salt thereof; and promethazine or a saltthereof. Furthermore, the oxycodone or a salt thereof is present in arange of about 1 mg to about 200 mg, including but not limited to 1.0mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg or 20mg, 30 mg, 40 mg, 50 mg, 70 mg, 100 mg, 130 mg, 160, 190 mg, 200 mg.Furthermore, the acetaminophen or a salt thereof is in a range ofbetween about 200 mg to about 1000 mg, including but not limited to 200mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 326 mg,326.5 mg, 327 mg, 327.5 mg, 328 mg, 328.5 mg, 329 mg, 329.5 mg, 330 mg,330.5 mg, 331 mg, 331.5 mg, 332 mg, 332.5 mg, 333 mg, 333.5 mg, 334 mg,334.5 mg, 335 mg, 335.5 mg, 336 mg, 336.5 mg, 337 mg, 337.5 mg, 338 mg,338.5 mg, 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg, 341.5 mg, 342 mg,342.5 mg, 343 mg, 343.5 mg, 344 mg, 344.5 mg, 345 mg, 345.5 mg, 346 mg,346.5 mg, 347 mg, 347.5 mg, 348 mg, 348.5 mg, 349 mg, 349.5 mg, 350 mg,350.5 mg, 351 mg, 351.5 mg, 352 mg, 352.5 mg, 353 mg, 353.5 mg, 354 mg,354.5 mg, 355 mg, 355.5 mg, 356 mg, 356.5 mg, 357 mg, 357.5 mg, 358 mg,358.5 mg, 359 mg, 359.5 mg, 360 mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg,362.5 mg, 363 mg, 363.5 mg, 364 mg, 364.5 mg, 365 mg, 365.5 mg, 366 mg,366.5 mg, 367 mg, 367.5 mg, 368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg,371.5 mg, 372 mg, 372.5 mg, 373 mg, 373.5 mg, 374 mg, 374.5 mg, 375 mg,375.5 mg, 376 mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, 378.5 mg, 379 mg,379.5 mg, 380 mg, 380.5 mg, 381 mg, 381.5 mg, 382 mg, 382.5 mg, 383 mg,383.5 mg, 384 mg, 384.5 mg, 385 mg, 385.5 mg, 386 mg, 386.5 mg, 387 mg,387.5 mg, 388 mg, 388.5 mg, 389 mg, 389.5 mg, 390 mg, 390.5 mg, 391 mg,391.5 mg, 392 mg, 392.5 mg, 393 mg, 393.5 mg, 394 mg, 394.5 mg, 395 mg,395.5 mg, 396 mg, 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5 mg, 399 mg,399.5 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660mg, 665 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935mg, 940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980mg, 985 mg, 990 mg, 995 mg, or 1000 mg. The compositions can furthercomprise between about 0.5 mg to about 200 mg of an antihistamine (e.g.,promethazine or a salt thereof), including but not limited to 0.5 mg,1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg,5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg,10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg,35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg, 44 mg, 45mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg,125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg,170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg. In oneembodiment oxycodone or a salt thereof, acetaminophen or a salt thereofand promethazine or a salt thereof are present in a bi-layer tablet thatcomprises an immediate release and a controlled release layer.

In one embodiment, the composition comprises promethazine or a saltthereof in an amount of 12.5 mg. In one embodiment, the compositions ofthe invention comprise oxycodone or a salt thereof, acetaminophen or asalt thereof and promethazine or a salt thereof, wherein the compositioncomprises the agents in a weight ratio of about (1 to 2):(40 to 45):(1to 2), respectively. In one embodiment a pharmaceutically acceptablesalt of oxycodone, acetaminophen orpromethazine is provided. Forexample, in one embodiment, the weight ratio of amounts for each activeagent is about (1):(43.33):(1.67) for oxycodone or a salt thereof,acetaminophen or a salt thereof and promethazine or a salt thereof,respectively. In one embodiment, the compositions of the inventioncomprise an antihistamine (e.g., promethazine or a salt thereof) at alower dosage than that which the antihistamine is administered alone. Inone embodiment, the antihistamine is provided in the composition at adosage to prevent sedation, which may be observed with relatively higherdosages of promethazine or a salt thereof. Thus in some embodiments,promethazine is provided at 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg,12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg,16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg,21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg,25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg,30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40mg, 41 mg, 12 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190mg, 195 mg, or 200 mg. Therefore, an antihistamine or antiemetic (e.g.,promethazine or a salt thereof) can be provided at a dosage that iseffective for reducing adverse affects associated with the opioidanalgesic or non-opioid analgesic, but is at a relative low enoughdosage (e.g., given the subject's weight) to prevent sedation associatedwith the antihistamine or antiemetic. Examples of adverse effectsinclude acute liver toxicity, allergic reactions such as swelling,difficulty breathing, closing of throat, abdominal pain, nausea, unusualbleeding or bruising. In one embodiment oxycodone or a salt thereof,acetaminophen or a salt thereof; and promethazine or a salt thereof arepresent in a bi-layer tablet that comprises an immediate release and acontrolled release layer.

In one embodiment, the compositions of the invention comprise 6-8 mg ofhydrocodone or a salt thereof (such as about 6.0 mg, 6.1 mg, 6.2 mg, 6.3mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7.0 mg, 7.1 mg, 7.2mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, or 8.0 mg),310-330 mg of acetaminophen (such as about 310 mg, 315 mg, 320 mg, or325 mg), and 5-13 mg of promethazine or a salt thereof (such as about 10mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13.0, mg, 13.5 mg, 14.0mg, 14.5 mg, or 15 mg). In a further embodiment a pharmaceuticallyacceptable salt of hydrocodone, acetaminophen or promethazine isprovided. The hydrocodone and the acetaminophen can be formulated usingconventional technologies to provide for an extended time release over adesired dosage interval. All or some of the promethazine can beformulated for immediate release to help abate common adverse effectsassociated with the hydrocodone and acetaminophen including nausea,vomiting, other gastric upsets, skin rashes, allergic reactions such asswelling, difficulty breathing, closing of throat, abdominal pain,unusual bleeding or bruising, sedation, CNS depression, or respiratorydepression. In one embodiment hydrocodone, acetaminophen; andpromethazine are present in a bi-layer tablet that comprises animmediate release and a controlled release layer.

In one embodiment, the compositions of the invention comprise from 1% to20% by weight of an antihistamine (such as 1%, 1.5%, 2%, 2.5%, 3%, 3.5%,4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%,11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%,17%, 17.5%, 18%, 18.5%, 19%, 19.5%, or 20%); from 10% to 80% by weight anon-opioid analgesic (such as 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%,13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%,19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%,25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 30.5%, 31%,31.5%, 32%, 32.5%, 33%, 33.5%, 34%, 34.5%, 35%, 35.5%, 36%, 36.5%, 37%,37.5%, 38%, 38.5%, 39%, 39.5%, 40%, 40.5%, 41%, 41.5%, 42%, 42.5%, 43%,43.5%, 44%, 44.5%, 45%, 45.5%, 46%, 46.5%, 47%, 47.5%, 48%, 48.5%, 49%,49.5%, 50%, 50.5%, 51%, 51.5%, 52%, 52.5%, 53%, 53.5%, 54%, 54.5%, 55%,55.5%, 56%, 56.5%, 57%, 57.5%, 58%, 58.5%, 59%, 59.5%, 60%, 60.5%, 61%,61.5%, 62%, 62.5%, 63%, 63.5%, 64%, 64.5%, 65%, 65.5%, 66%, 66.5%, 67%,67.5%, 68%, 68.5%, 69%, 69.5%, 70%, 70.5%, 71%, 71.5%, 72%, 72.5%, 73%,73.5%, 74%, 74.5%, 75%, 75.5%, 76%, 76.5%, 77%, 77.5%, 78%, 78.5%, 79%,79.5%, 80%); and from 1% to 20% by weight of an opioid analgesic (suchas 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%,8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%,14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, or20%). In one embodiment an opioid analgesic agent, a non-opioidanalgesic and an antihistamine are present in a bi-layer tablet thatcomprises an immediate release and a controlled release layer.

In one embodiment, the compositions of the invention comprise 6-8 mg ofoxycodone HCL (such as about 7.5 mg), 310-330 mg of acetaminophen (suchas about 325 mg), and 6-15 mg of promethazine HCL (such as about 12.5mg). The oxycodone HCL and the acetaminophen can be formulated usingconventional technologies to provide for an extended time release over adesired dosage interval. All or some of the promethazine can beformulated for immediate release. In one embodiment the composition isin the form of a bi-layer tablet comprising an immediate-release layercomprising promethazine HCL and a controlled-release layer and acontrolled release layer comprising acetaminophen and oxycodone or asalt thereof.

In one embodiment, administration of the composition disclosed hereinthat comprises an antiemetic agent (such as promethazine or a saltthereof) can produce an outcome in a subject, such as reduced, abated oreliminated adverse effects associated with the administration of anopioid agent or non-opioid agent, such as oxycodone HCL, hydrocodonebitartrate and acetaminophen. Reduced, abated or eliminated adverseeffects include but are not limited to including nausea, vomiting, othergastric upsets, skin rashes, allergic reactions such as swelling,difficulty breathing, closing of throat, abdominal pain, unusualbleeding or bruising, sedation, CNS depression, or respiratorydepression or any combination thereof.

The dosages and concentrations of active agents in the compositions maybe varied as desired, as further described herein. Depending on thesubject and/or condition being treated and on the administration route,the active agent in a composition can generally be administered indosages of 0.01 mg to 500 mg per kg body weight per day, e.g. about 20mg/day for an average person. The dosage can be adjusted based on themode of administration. A typical dosage may be one administration dailyor multiple administrations daily.

Of course for controlled-release dosage forms the unit dose can bedesigned for administration over a defined period of time. In someembodiments, dosage for one or a combination of agents can be from about0.01 to 5 mg, 1 to 10 mg, 5 to 20 mg, 10 to 50 mg, 20 to 100 mg, 50 to150 mg, 100 to 250 mg, 150 to 300 mg, 250 to 500 mg, 300 to 600 mg or500 to 1000 mg V/kg body weight. Dose levels can vary as a function ofthe specific compound, the severity of the symptoms and thesusceptibility of the subject to adverse effects.

In another embodiment a composition comprises multiple active agents atthe same or different dosages, where the composition comprises aneffective amount of: an opioid analgesic; an antiemetic orantihistamine; and a stimulant. In some embodiments the composition mayfurther comprise a barbiturate or a non-opioid active agent, or both.The dosage can be adjusted according to the particular actives selected.

In one embodiment, a composition comprises an effective amount of: anopioid analgesic; an antiemetic or antihistamine; and a stimulant. Inthis embodiment the antiemetic or an antihistamine (e.g., promethazineor a salt thereof), that is present at about 0.5 mg to about 60 mg,including but not limited to a dose of about 0.5 mg, 1.0 mg, 1.5 mg, 2.0mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg,15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg,20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg,24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg,29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg,38 mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48mg, 49 mg, 50 mg, 55 mg, 60 mg. In one embodiment, the antiemetic orantihistamine is promethazine or a salt thereof. In various otherembodiments, the antihistamine or antiemetic is one described hereinabove. As described herein, in some embodiments, the antihistamine orantiemetic is a component of an immediate-release formulation. Forexample, in a further embodiment, the immediate-release is in a capsule,a tablet, a transdermal means, or achieved through injection,intramuscular administration or other means disclosed herein. In oneembodiment an opioid analgesic agent, a stimulant and an antihistamineare present in a bi-layer tablet that comprises an immediate release anda controlled release layer. In one embodiment the stimulant and anantihistamine are present in the immediate release layer and the opioidanalgesic agent is present in the controlled release layer. In anotherembodiment an opioid analgesic agent, a non-opioid analgesic, astimulant and an antihistamine are present in a bi-layer tablet thatcomprises an immediate release and a controlled release layer. In oneembodiment the stimulant and an antihistamine are present in theimmediate release layer and the opioid analgesic agent and a non-opioidanalgesic are present in the controlled release layer.

In a further embodiment, a composition of the invention comprises: aneffective amount of an opioid analgesic agent; an antiemetic orantihistamine agent; and a stimulant agent or a non-opioid agent, orboth. In one embodiment each agent is present at a dose of about 0.5 mgto about 20 mg, 5 mg to 30 mg, 10 mg to 100 mg, including but notlimited to about 0.5 mg, 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg,6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0,10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg,15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg,19.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg. In oneembodiment an opioid analgesic agent, a stimulant and an antihistamineare present in a bi-layer tablet that comprises an immediate release anda controlled release layer. In one embodiment the stimulant and anantihistamine are present in the immediate release layer and the opioidanalgesic agent is present in the controlled release layer.

In yet a further embodiment, the composition comprising: an effectiveamount of an opioid analgesic, a stimulant and optionally an antiemeticor antihistamine. In one embodiment the composition comprises astimulant at a dose of about 1 mg to about 350 mg, 5 mg to 25 mg, 10 mgto 50 mg, 25 to 100 mg, 50 to 150 mg, 100 mg to 250 mg, 75 mg to 350 mg,including but not limited to about 1.0 mg, 1.0 mg, 1.5 mg, 2.5 mg, 3.0mg, 4.0 mg, 5.0 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg,14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg,50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320mg, 330 mg, 340 mg, or 350 mg. In one embodiment an opioid analgesicagent, a stimulant and an antihistamine are present in a bi-layer tabletthat comprises an immediate release and a controlled release layer. Inone embodiment the stimulant and an antihistamine are present in theimmediate release layer and the opioid analgesic agent is present in thecontrolled release layer.

In various embodiments, a composition of the invention comprises: anopioid analgesic, a stimulant, and an antiemetic or antihistamine,wherein the relative ratio by weight of each of an opioid:a stimulant:anantiemetic or antihistamine is about (1 to 2):(40 to 45):(1 to 2), suchas about 1:40:1, 1:40:1.1, 1:40:1.2, 1:40:1.3, 1:40:1.4, 1:40:1.5,1:40:1.6, 1:40:1.7, 1:40:1.8, 1:40:1.9, 1:40:2, 1.1:40:1, 1.2:40:1,1.3:40:1, 1.4:40:1, 1.5:40:1, 1.6:40:1, 1.7:40:1, 1.8:40:1, 1.9:40:1,2:40:1, 1:41:1, 1:41:1.1, 1:41:1.2, 1:41:1.3, 1:41:1.4, 1:41:1.5,1:41:1.6, 1:41:1.7, 1:41:1.8, 1:41:1.9, 1:41:2, 1.1:41:1, 1.2:41:1,1.3:41:1, 1.4:41:1, 1.5:41:1, 1.6:41:1, 1.7:41:1, 1.8:41:1, 1.9:41:1,2:41:1, 1:42:1, 1:42:1.1, 1:42:1.2, 1:42:1.3, 1:42:1.4, 1:42:1.5,1:42:1.6, 1:42:1.7, 1:42:1.8, 1:42:1.9, 1:42:2, 1.1:42:1, 1.2:42:1,1.3:42:1, 1.4:42:1, 1.5:42:1, 1.6:42:1, 1.7:42:1, 1.8:42:1, 1.9:42:1,2:42:1, 1:43:1, 1:43:1.1, 1:43:1.2, 1:43:1.3, 1:43:1.4, 1:43:1.5,1:43:1.6, 1:43:1.7, 1:43:1.8, 1:43:1.9, 1:43:2, 1.1:43:1, 1.2:43:1,1.3:43:1, 1.4:43:1, 1.5:43:1, 1.6:43:1, 1.7:43:1, 1.8:43:1, 1.9:43:1,2:43:1, 1:43.1:1, 1:43.1:1.1, 1:43.1:1.2, 1:43.1:1.3, 1:43.1:1.4,1:43.1:1.5, 1:43.1:1.6, 1:43.1:1.7, 1:43.1:1.8, 1:43.1:1.9, 1:43.1:2,1.1:43.1:1, 1.2:43.1:1, 1.3:43.1:1, 1.4:43.1:1, 1.5:43.1:1, 1.6:43.1:1,1.7:43.1:1, 1.8:43.1:1, 1.9:43.1:1, 2:43.1:1, 1:43.2:1, 1:43.2:1.1,1:43.2:1.2, 1:43.2:1.3, 1:43.2:1.4, 1:43.2:1.5, 1:43.2:1.6, 1:43.2:1.7,1:43.2:1.8, 1:43.2:1.9, 1:43.2:2, 1.1:43.2:1, 1.2:43.2:1, 1.3:43.2:1,1.4:43.2:1, 1.5:43.2:1, 1.6:43.2:1, 1.7:43.2:1, 1.8:43.2:1, 1.9:43.2:1,2:43.2:1, 1:43.3:1, 1:43.3:1.1, 1:43.3:1.2, 1:43.3:1.3, 1:43.3:1.4,1:43.3:1.5, 1:43.3:1.6, 1:43.3:1.7, 1:43.3:1.8, 1:43.3:1.9, 1:43.3:2,1.1:43.3:1, 1.2:43.3:1, 1.3:43.3:1, 1.4:43.3:1, 1.5:43.3:1, 1.6:43.3:1,1.7:43.3:1, 1.8:43.3:1, 1.9:43.3:1, 2:43.3:1, 1:43.4:1, 1:43.4:1.1,1:43.4:1.2, 1:43.4:1.3, 1:43.4:1.4, 1:43.4:1.5, 1:43.4:1.6, 1:43.4:1.7,1:43.4:1.8, 1:43.4:1.9, 1:43.4:2, 1.1:43.4:1, 1.2:43.4:1, 1.3:43.4:1,1.4:43.4:1, 1.5:43.4:1, 1.6:43.4:1, 1.7:43.4:1, 1.8:43.4:1, 1.9:43.4:1,2:43.4:1, 1:43.5:1, 1:43.5:1.1, 1:43.5:1.2, 1:43.5:1.3, 1:43.5:1.4,1:43.5:1.5, 1:43.5:1.6, 1:43.5:1.7, 1:43.5:1.8, 1:43.5:1.9, 1:43.5:2,1.1:43.5:1, 1.2:43.5:1, 1.3:43.5:1, 1.4:43.5:1, 1.5:43.5:1, 1.6:43.5:1,1.7:43.5:1, 1.8:43.5:1, 1.9:43.5:1, 2:43.5:1, 1:43.6:1, 1:43.6:1.1,1:43.6:1.2, 1:43.6:1.3, 1:43.6:1.4, 1:43.6:1.5, 1:43.6:1.6, 1:43.6:1.7,1:43.6:1.8, 1:43.6:1.9, 1:43.6:2, 1.1:43.6:1, 1.2:43.6:1, 1.3:43.6:1,1.4:43.6:1, 1.5:43.6:1, 1.6:43.6:1, 1.7:43.6:1, 1.8:43.6:1, 1.9:43.6:1,2:43.6:1, 1:43.7:1, 1:43.7:1.1, 1:43.7:1.2, 1:43.7:1.3, 1:43.7:1.4,1:43.7:1.5, 1:43.7:1.6, 1:43.7:1.7, 1:43.7:1.8, 1:43.7:1.9, 1:43.7:2,1.1:43.7:1, 1.2:43.7:1, 1.3:43.7:1, 1.4:43.7:1, 1.5:43.7:1, 1.6:43.7:1,1.7:43.7:1, 1.8:43.7:1, 1.9:43.7:1, 2:43.7:1, 1:43.8:1, 1:43.8:1.1,1:43.8:1.2, 1:43.8:1.3, 1:43.8:1.4, 1:43.8:1.5, 1:43.8:1.6, 1:43.8:1.7,1:43.8:1.8, 1:43.8:1.9, 1:43.8:2, 1.1:43.8:1, 1.2:43.8:1, 1.3:43.8:1,1.4:43.8:1, 1.5:43.8:1, 1.6:43.8:1, 1.7:43.8:1, 1.8:43.8:1, 1.9:43.8:1,2:43.8:1, 1:43.9:1, 1:43.9:1.1, 1:43.9:1.2, 1:43.9:1.3, 1:43.9:1.4,1:43.9:1.5, 1:43.9:1.6, 1:43.9:1.7, 1:43.9:1.8, 1:43.9:1.9, 1:43.9:2,1.1:43.9:1, 1.2:43.9:1, 1.3:43.9:1, 1.4:43.9:1, 1.5:43.9:1, 1.6:43.9:1,1.7:43.9:1, 1.8:43.9:1, 1.9:43.9:1, 2:43.9:1, 1:44:1, 1:44:1.1,1:44:1.2, 1:44:1.3, 1:44:1.4, 1:44:1.5, 1:44:1.6, 1:44:1.7, 1:44:1.8,1:44:1.9, 1:44:2, 1.1:44:1, 1.2:44:1, 1.3:44:1, 1.4:44:1, 1.5:44:1,1.6:44:1, 1.7:44:1, 1.8:44:1, 1.9:44:1, 2:44:1, 1:45:1, 1:45:1.1,1:45:1.2, 1:45:1.3, 1:45:1.4, 1:45:1.5, 1:45:1.6, 1:45:1.7, 1:45:1.8,1:45:1.9, 1:45:2, 1.1:45:1, 1.2:45:1, 1.3:45:1, 1.4:45:1, 1.5:45:1,1.6:45:1, 1.7:45:1, 1.8:45:1, 1.9:45:1, or 2:45:1. In one embodiment anopioid analgesic agent, a stimulant and an antihistamine are present ina bi-layer tablet that comprises an immediate release and a controlledrelease layer. In one embodiment the stimulant and an antihistamine arepresent in the immediate release layer and the opioid analgesic agent ispresent in the controlled release layer.

In another embodiment, compositions are provided that comprise aneffective amount of an opioid (such as hydrocodone, fentanyl oroxycodone or a salt thereof); a non-opioid (such as acetaminophen ornaproxen salt thereof); and a barbiturate (such as butalbital or a saltthereof). In some embodiments the compositions further comprise anantiemetic (such as promethazine or a salt thereof). In some embodimentsthe composition further comprises a stimulant agent. In some embodimentsthe barbiturate is present at a dose of 1 mg to about 350 mg, 5 mg to 25mg, 10 mg to 50 mg, 25 to 100 mg, 50 to 150 mg, 100 mg to 250 mg, 75 mgto 350 mg, including but not limited to about 1.0 mg, 1.0 mg, 1.5 mg,2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg,8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg,17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg,130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg,220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg,310 mg, 320 mg, 330 mg, 340 mg, or 350 mg.

In another embodiment the compositions comprise an effective amount ofan opioid (such as hydrocodone, fentanyl or oxycodone or a saltthereof); a non-opioid agent (such as acetaminophen or naproxen or asalt thereof); and a barbiturate (such as butalbital or a salt thereof).In one embodiment the opioid agent (such as hydrocodone or oxycodone ora salt thereof) is present in a range of about 1 mg to about 200 mg,including but not limited to 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 4.5mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg,14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18mg, 18.5 mg, 19 mg, 19.5 mg or 20 mg, 30 mg, 40 mg, 50 mg, 70 mg, 100mg, 130 mg, 160, 190 mg, 200 mg. Furthermore, the non-opioid agent (suchas acetaminophen or naproxen or a salt thereof) is present in a range ofbetween about 200 mg to about 1000 mg, including but not limited to 200mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 326 mg,326.5 mg, 327 mg, 327.5 mg, 328 mg, 328.5 mg, 329 mg, 329.5 mg, 330 mg,330.5 mg, 331 mg, 331.5 mg, 332 mg, 332.5 mg, 333 mg, 333.5 mg, 334 mg,334.5 mg, 335 mg, 335.5 mg, 336 mg, 336.5 mg, 337 mg, 337.5 mg, 338 mg,338.5 mg, 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg, 341.5 mg, 342 mg,342.5 mg, 343 mg, 343.5 mg, 344 mg, 344.5 mg, 345 mg, 345.5 mg, 346 mg,346.5 mg, 347 mg, 347.5 mg, 348 mg, 348.5 mg, 349 mg, 349.5 mg, 350 mg,350.5 mg, 351 mg, 351.5 mg, 352 mg, 352.5 mg, 353 mg, 353.5 mg, 354 mg,354.5 mg, 355 mg, 355.5 mg, 356 mg, 356.5 mg, 357 mg, 357.5 mg, 358 mg,358.5 mg, 359 mg, 359.5 mg, 360 mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg,362.5 mg, 363 mg, 363.5 mg, 364 mg, 364.5 mg, 365 mg, 365.5 mg, 366 mg,366.5 mg, 367 mg, 367.5 mg, 368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg,371.5 mg, 372 mg, 372.5 mg, 373 mg, 373.5 mg, 374 mg, 374.5 mg, 375 mg,375.5 mg, 376 mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, 378.5 mg, 379 mg,379.5 mg, 380 mg, 380.5 mg, 381 mg, 381.5 mg, 382 mg, 382.5 mg, 383 mg,383.5 mg, 384 mg, 384.5 mg, 385 mg, 385.5 mg, 386 mg, 386.5 mg, 387 mg,387.5 mg, 388 mg, 388.5 mg, 389 mg, 389.5 mg, 390 mg, 390.5 mg, 391 mg,391.5 mg, 392 mg, 392.5 mg, 393 mg, 393.5 mg, 394 mg, 394.5 mg, 395 mg,395.5 mg, 396 mg, 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5 mg, 399 mg,399.5 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660mg, 665 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935mg, 940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980mg, 985 mg, 990 mg, 995 mg, or 1000 mg. Additionally, the barbiturate(e.g., butalbital or a salt thereof) is present at a dose between about0.5 mg to about 200 mg, including but not limited to, 0.5 mg, 1.0 mg,1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg,6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg,10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg,36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg, 44 mg, 45 mg, 46mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg,130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg,175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg. In one embodiment anopioid analgesic agent, a non-opioid agent, and a barbiturate agent arepresent in a bi-layer tablet that comprises an immediate release and acontrolled release layer. In a further embodiment the bi-layer tabletcomprises an antiemetic agent, such as an antihistamine. In oneembodiment the antihistamine is present in the immediate release layerand the opioid analgesic agent, non-opioid agent, and barbiturate agentare present in the controlled release layer.

In another embodiment compositions are provided that comprise aneffective amount of a barbiturate agent (such as butalbital or a saltthereof); a non-opioid agent (such as acetaminophen or naproxen or asalt thereof); and a stimulant agent (such as caffeine or a saltthereof). In one embodiment the barbiturate agent (such as butalbital ora salt thereof); is present in a range of about 0.5 mg to about 200 mg,including but not limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg,12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg,16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg,21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg,25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg,30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40mg, 41 mg, 12 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190mg, 195 mg, or 200 mg. Furthermore, the non-opioid agent (such asacetaminophen or naproxen or a salt thereof) is present in a range ofbetween about 200 mg to about 1000 mg, including but not limited to 200mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 326 mg,326.5 mg, 327 mg, 327.5 mg, 328 mg, 328.5 mg, 329 mg, 329.5 mg, 330 mg,330.5 mg, 331 mg, 331.5 mg, 332 mg, 332.5 mg, 333 mg, 333.5 mg, 334 mg,334.5 mg, 335 mg, 335.5 mg, 336 mg, 336.5 mg, 337 mg, 337.5 mg, 338 mg,338.5 mg, 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg, 341.5 mg, 342 mg,342.5 mg, 343 mg, 343.5 mg, 344 mg, 344.5 mg, 345 mg, 345.5 mg, 346 mg,346.5 mg, 347 mg, 347.5 mg, 348 mg, 348.5 mg, 349 mg, 349.5 mg, 350 mg,350.5 mg, 351 mg, 351.5 mg, 352 mg, 352.5 mg, 353 mg, 353.5 mg, 354 mg,354.5 mg, 355 mg, 355.5 mg, 356 mg, 356.5 mg, 357 mg, 357.5 mg, 358 mg,358.5 mg, 359 mg, 359.5 mg, 360 mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg,362.5 mg, 363 mg, 363.5 mg, 364 mg, 364.5 mg, 365 mg, 365.5 mg, 366 mg,366.5 mg, 367 mg, 367.5 mg, 368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg,371.5 mg, 372 mg, 372.5 mg, 373 mg, 373.5 mg, 374 mg, 374.5 mg, 375 mg,375.5 mg, 376 mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, 378.5 mg, 379 mg,379.5 mg, 380 mg, 380.5 mg, 381 mg, 381.5 mg, 382 mg, 382.5 mg, 383 mg,383.5 mg, 384 mg, 384.5 mg, 385 mg, 385.5 mg, 386 mg, 386.5 mg, 387 mg,387.5 mg, 388 mg, 388.5 mg, 389 mg, 389.5 mg, 390 mg, 390.5 mg, 391 mg,391.5 mg, 392 mg, 392.5 mg, 393 mg, 393.5 mg, 394 mg, 394.5 mg, 395 mg,395.5 mg, 396 mg, 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5 mg, 399 mg,399.5 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660mg, 665 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935mg, 940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980mg, 985 mg, 990 mg, 995 mg, or 1000 mg. Additionally, the stimulantagent (e.g., caffeine) is present at a dose from about 0.5 mg to about200 mg including but not limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg,11.5 mg, 12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29mg, 29.5 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38mg, 39 mg, 40 mg, 41 mg, 12 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48mg, 49 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180mg, 185 mg, 190 mg, 195 mg, or 200 mg. In one embodiment a stimulantagent, a non-opioid agent, and a barbiturate agent are present in abi-layer tablet that comprises an immediate release and a controlledrelease layer. In one embodiment the stimulant is present in theimmediate release layer and the non-opioid analgesic agent andbarbiturate are present in the controlled release layer. In a furtherembodiment the bi-layer tablet comprises an antiemetic agent, such as anantihistamine (e.g., promethazine). In one embodiment the stimulant andan antihistamine are present in the immediate release layer and thenon-opioid analgesic agent and barbiturate are present in the controlledrelease layer.

In another embodiment compositions are provided that comprise aneffective amount of a barbiturate and a stimulant. In one embodiment thecomposition comprises a stimulant at a dose of about 1 mg to about 350mg (such as 5 mg to 25 mg, 10 mg to 50 mg, 25 to 100 mg, 50 to 150 mg,100 mg to 250 mg, 75 mg to 350 mg) including but not limited to about1.0 mg, 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 6.5 mg,7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0 mg,12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg,16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg,25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg,100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg,190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg,280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, or 350 mg.Additionally, the barbiturate agent (such as butalbital or a saltthereof); is present in a range of about 0.5 mg to about 200 mg,including but not limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg,12.0 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg,16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg,21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg,25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg,30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40mg, 41 mg, 12 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190mg, 195 mg, or 200 mg. In one embodiment, a barbiturate agent, and astimulant are present in a bi-layer tablet that comprises an immediaterelease and a controlled release layer. In a further embodiment thebi-layer tablet further comprises an antiemetic agent, such as anantihistamine (e.g. promethazine or a salt thereof). In one embodimentthe stimulant and an antihistamine are present in the immediate releaselayer and the barbiturate agent is present in the controlled releaselayer.

In another embodiment the compositions comprise an effective amount of anon-opioid agent (such as naproxen or ibuprofen or a salt thereof) and astimulant (such as caffeine or a salt thereof). In some embodiments thenon-opioid agent (such as naproxen or ibuprofen or a salt thereof) ispresent in a range of between about 200 mg to about 1000 mg, includingbut not limited to 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320mg, 325 mg, 326 mg, 326.5 mg, 327 mg, 327.5 mg, 328 mg, 328.5 mg, 329mg, 329.5 mg, 330 mg, 330.5 mg, 331 mg, 331.5 mg, 332 mg, 332.5 mg, 333mg, 333.5 mg, 334 mg, 334.5 mg, 335 mg, 335.5 mg, 336 mg, 336.5 mg, 337mg, 337.5 mg, 338 mg, 338.5 mg, 339 mg, 339.5 mg, 340 mg, 340.5 mg, 341mg, 341.5 mg, 342 mg, 342.5 mg, 343 mg, 343.5 mg, 344 mg, 344.5 mg, 345mg, 345.5 mg, 346 mg, 346.5 mg, 347 mg, 347.5 mg, 348 mg, 348.5 mg, 349mg, 349.5 mg, 350 mg, 350.5 mg, 351 mg, 351.5 mg, 352 mg, 352.5 mg, 353mg, 353.5 mg, 354 mg, 354.5 mg, 355 mg, 355.5 mg, 356 mg, 356.5 mg, 357mg, 357.5 mg, 358 mg, 358.5 mg, 359 mg, 359.5 mg, 360 mg, 360.5 mg, 361mg, 361.5 mg, 362 mg, 362.5 mg, 363 mg, 363.5 mg, 364 mg, 364.5 mg, 365mg, 365.5 mg, 366 mg, 366.5 mg, 367 mg, 367.5 mg, 368 mg, 369.5 mg, 370mg, 370.5 mg, 371 mg, 371.5 mg, 372 mg, 372.5 mg, 373 mg, 373.5 mg, 374mg, 374.5 mg, 375 mg, 375.5 mg, 376 mg, 376.5 mg, 377 mg, 377.5 mg, 378mg, 378.5 mg, 379 mg, 379.5 mg, 380 mg, 380.5 mg, 381 mg, 381.5 mg, 382mg, 382.5 mg, 383 mg, 383.5 mg, 384 mg, 384.5 mg, 385 mg, 385.5 mg, 386mg, 386.5 mg, 387 mg, 387.5 mg, 388 mg, 388.5 mg, 389 mg, 389.5 mg, 390mg, 390.5 mg, 391 mg, 391.5 mg, 392 mg, 392.5 mg, 393 mg, 393.5 mg, 394mg, 394.5 mg, 395 mg, 395.5 mg, 396 mg, 396.5 mg, 397 mg, 397.5 mg, 398mg, 398.5 mg, 399 mg, 399.5 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg,425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg,470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg,515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg,560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg,605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg,650 mg, 655 mg, 660 mg, 665 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg,700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg,745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg,790 mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg,835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg,880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg,925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg,970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 995 mg, or 1000 mg. In theseembodiments the compositions comprise a stimulant at a dose of about 1mg to about 350 mg, (such as 5 mg to 25 mg, 10 mg to 50 mg, 25 to 100mg, 50 to 150 mg, 100 mg to 250 mg, or 75 mg to 350 mg), including butnot limited to about 1.0 mg, 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg,10.0, 10.5 mg, 11.0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg,14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5mg, 19 mg, 19.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg,160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg,250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg,340 mg, or 350 mg. In one embodiment a non-opioid agent and a stimulantare formulated as a bi-layer tablet that comprises an immediate releaseand a controlled release layer. In one example naproxen and caffeine areformulated in a bi-layer tablet. In one embodiment the caffeine ispresent in the immediate release layer and naproxen is present in thecontrolled release layer.

In one embodiment, the compositions of the invention comprise aneffective amount of propoxyphene or a salt thereof and a non-opioidagent (such as naproxen or a salt thereof). In some embodiments thecomposition further comprises an antiemetic (such as promethazine or asalt thereof). In some embodiments the compositions further comprise astimulant agent. In one embodiment, the propoxyphene or salt thereof ispresent in a range of about 1.0 mg to about 100 mg, including but notlimited to 11.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 6.5mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0, 10.5 mg, 11.0mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29mg, 29.5 mg, 30 mg, 30.5 mg, 31 mg, 31.5 mg, 32 mg, 32.5 mg, 33 mg, 33.5mg, 36 mg, 36.5 mg, 37 mg, 37.5 mg, 38 mg, 38.5 mg, 39 mg, 39.5 mg, 40mg, 40.5 mg, 41 mg, 41.5 mg, 42 mg, 42.5 mg, 43 mg, 43.5 mg, 44 mg, 44.5mg, 45 mg, 45.5 mg, 46 mg, 46.5 mg, 47 mg, 47.5 mg, 48 mg, 48.5 mg, 49mg, 49.5 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90mg, 95 mg, or 100 mg. Furthermore, the non-opioid agent is in a range ofabout 200 mg to about 1000 mg, including but not limited to 200 mg, 205mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 326 mg, 326.5 mg,327 mg, 327.5 mg, 328 mg, 328.5 mg, 329 mg, 329.5 mg, 330 mg, 330.5 mg,331 mg, 331.5 mg, 332 mg, 332.5 mg, 333 mg, 333.5 mg, 334 mg, 334.5 mg,335 mg, 335.5 mg, 336 mg, 336.5 mg, 337 mg, 337.5 mg, 338 mg, 338.5 mg,339 mg, 339.5 mg, 340 mg, 340.5 mg, 341 mg, 341.5 mg, 342 mg, 342.5 mg,343 mg, 343.5 mg, 344 mg, 344.5 mg, 345 mg, 345.5 mg, 346 mg, 346.5 mg,347 mg, 347.5 mg, 348 mg, 348.5 mg, 349 mg, 349.5 mg, 350 mg, 350.5 mg,351 mg, 351.5 mg, 352 mg, 352.5 mg, 353 mg, 353.5 mg, 354 mg, 354.5 mg,355 mg, 355.5 mg, 356 mg, 356.5 mg, 357 mg, 357.5 mg, 358 mg, 358.5 mg,359 mg, 359.5 mg, 360 mg, 360.5 mg, 361 mg, 361.5 mg, 362 mg, 362.5 mg,363 mg, 363.5 mg, 364 mg, 364.5 mg, 365 mg, 365.5 mg, 366 mg, 366.5 mg,367 mg, 367.5 mg, 368 mg, 369.5 mg, 370 mg, 370.5 mg, 371 mg, 371.5 mg,372 mg, 372.5 mg, 373 mg, 373.5 mg, 374 mg, 374.5 mg, 375 mg, 375.5 mg,376 mg, 376.5 mg, 377 mg, 377.5 mg, 378 mg, 378.5 mg, 379 mg, 379.5 mg,380 mg, 380.5 mg, 381 mg, 381.5 mg, 382 mg, 382.5 mg, 383 mg, 383.5 mg,384 mg, 384.5 mg, 385 mg, 385.5 mg, 386 mg, 386.5 mg, 387 mg, 387.5 mg,388 mg, 388.5 mg, 389 mg, 389.5 mg, 390 mg, 390.5 mg, 391 mg, 391.5 mg,392 mg, 392.5 mg, 393 mg, 393.5 mg, 394 mg, 394.5 mg, 395 mg, 395.5 mg,396 mg, 396.5 mg, 397 mg, 397.5 mg, 398 mg, 398.5 mg, 399 mg, 399.5 mg,400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg,445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg,490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg,535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg,580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg,625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg,675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg,720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg,765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg,810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg,855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg,900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg,945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg,990 mg, 995 mg, or 1000 mg. In one embodiment propoxyphene or a saltthereof and naproxen (such as naproxen sodium or naproxen magnesium) arepresent in a bi-layer tablet. In a further embodiment, the compositioncomprises an antiemetic or an antihistamine (e.g., promethazine or asalt thereof). In one embodiment the antihistamine is present in theimmediate release layer and propoxyphene and naproxen are present in thecontrolled release layer.

In another embodiment, the compositions described herein comprise aneffective amount of an antiemetic or an antihistamine (e.g.,promethazine or a salt thereof), that is present in the range of atabout 0.5 mg to about 60 mg, including but not limited to a dose ofabout 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg,4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg,9.0 mg, 9.5 mg, 10 mg, 10.5 mg, 11.0 mg, 11.5 mg, 12.0 mg, 12.5 mg, 13mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, 30 mg, 31 mg, 32 mg,33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 12 mg, 43mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 mg, 60 mg. Inone embodiment, the antiemetic or antihistamine is promethazine or asalt thereof. In various other embodiments, the antihistamine orantiemetic is another described herein above. As described herein, insome embodiments, the antihistamine or antiemetic is a component of animmediate-release formulation. For example, in a further embodiment, theimmediate-release is in a lollipop, capsule, a tablet, a transdermalmeans, through injection, intramuscular administration or other meansdisclosed herein.

Dosage Forms

Oral Dosage Forms

In one embodiment the invention relates to methods and compositionsformulated for oral delivery to a subject in need. In one embodiment acomposition is formulated so as to deliver one or more pharmaceuticallyactive agents to a subject through a mucosa layer in the mouth oresophagus. In another embodiment the composition is formulated todeliver one or more pharmaceutically active agents to a subject througha mucosa layer in the stomach and/or intestines.

In one embodiment compositions are provided in modified release dosageforms (such as immediate release, controlled release or both), whichcomprise an effective amount of an opioid analgesic (such as oxycodoneor hydrocodone or a salt thereof), a non-opioid analgesic (such asacetaminophen, naproxen or ibuprofen or a salt thereof) and anantihistamine (such as promethazine or a salt thereof); and one or morerelease controlling excipients as described herein. Suitable modifiedrelease dosage vehicles include, but are not limited to, hydrophilic orhydrophobic matrix devices, water-soluble separating layer coatings,enteric coatings, osmotic devices, multi-particulate devices, andcombinations thereof. The compositions may also comprise non-releasecontrolling excipients.

In another embodiment compositions are provided in enteric coated dosageforms. The compositions can also comprise non-release controllingexcipients.

In another embodiment compositions are provided in effervescent dosageforms. The compositions can also comprise non-release controllingexcipients.

In another embodiment compositions can be provided in a dosage form thathas at least one component that can facilitate the immediate release ofan active agent, and at least one component that can facilitate thecontrolled release of an active agent. In a further embodiment thedosage form can be capable of giving a discontinuous release of thecompound in the form of at least two consecutive pulses separated intime from 0.1 up to 24 hours. The compositions can comprise one or morerelease controlling and non-release controlling excipients, such asthose excipients suitable for a disruptable semi-permeable membrane andas swellable substances.

In another embodiment compositions are provided in a dosage form fororal administration to a subject, which comprise one or morepharmaceutically acceptable excipients or carriers, enclosed in anintermediate reactive layer comprising a gastric juice-resistantpolymeric layered material partially neutralized with alkali and havingcation exchange capacity and a gastric juice-resistant outer layer.

In one embodiment the compositions are in the form of enteric-coatedgranules, as controlled-release capsules for oral administration. Thecompositions can further comprise cellulose, disodium hydrogenphosphate, hydroxypropyl cellulose, hypromellose, lactose, mannitol, andsodium lauryl sulfate.

In another embodiment the compositions are in the form of enteric-coatedpellets, as controlled-release capsules for oral administration. Thecompositions can further comprise glyceryl monostearate 40-50,hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylicacid copolymer type C, polysorbate 80, sugar spheres, talc, and triethylcitrate.

In another embodiment the compositions are enteric-coatedcontrolled-release tablets for oral administration. The compositions canfurther comprise carnauba wax, crospovidone, diacetylatedmonoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellosephthalate, magnesium stearate, mannitol, sodium hydroxide, sodiumstearyl fumarate, talc, titanium dioxide, and yellow ferric oxide.

In another embodiment the compositions can further comprise calciumstearate, crospovidone, hydroxypropyl methylcellulose, iron oxide,mannitol, methacrylic acid copolymer, polysorbate 80, povidone,propylene glycol, sodium carbonate, sodium lauryl sulfate, titaniumdioxide, and triethyl citrate.

The compositions provided herein can be in unit-dosage forms ormultiple-dosage forms. Unit-dosage forms, as used herein, refer tophysically discrete units suitable for administration to human ornon-human animal subjects and packaged individually. Each unit-dose cancontain a predetermined quantity of an active ingredient(s) sufficientto produce the desired therapeutic effect, in association with therequired pharmaceutical carriers or excipients. Examples of unit-dosageforms include, but are not limited to, ampules, syringes, andindividually packaged tablets and capsules. Unit-dosage forms may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer, which can be administered in segregated unit-dosage form.Examples of multiple-dosage forms include, but are not limited to,vials, bottles of tablets or capsules, or bottles of pints or gallons.In another embodiment the multiple dosage forms comprise differentpharmaceutically active agents. For example a multiple dosage form canbe provided which comprises a first dosage element comprising animmediate release form of an antihistamine (such as in a liquid form)and a second dosage element comprising an opioid and/or non opioidanalgesic, which can be in a modified release form (such as immediaterelease, controlled release, or extended release form).

In this example a pair of dosage elements can make a single unit dosage.In one embodiment a kit is provided comprising multiple unit dosages,wherein each unit comprises a first dosage element comprising animmediate release form of an antihistamine (such as in a liquid form)and a second dosage element comprising an opioid or non-opioid analgesicor both, which can be in a modified release form (such as immediaterelease or controlled release, or both). In another embodiment the kitfurther comprises a set of instructions. In yet a further embodiment theantihistamine is promethazine or a pharmaceutically acceptable saltthereof, the opioid analgesic is oxycodone or hydrocodone orpharmaceutically acceptable salt thereof, the non-opioid analgesic isacetaminophen or a pharmaceutically acceptable salt thereof.

In one embodiment compositions can be formulated in various dosage formsfor oral, parenteral, and topical administration. The compositions mayalso be formulated as a modified release dosage form, includingimmediate-, delayed-, extended-, prolonged-, sustained-, pulsatile-,controlled-, extended, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. These dosageforms can be prepared according to known methods and techniques (see,Remington: The Science and Practice of Pharmacy, supra; Modified-ReleaseDrug Delivery Technology, Rathbone et al., Eds., Drugs and thePharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol.126, which is herein incorporated by reference in its entirety).

In various embodiments of the invention, the compositions are in one ormore dosage form. For example, a composition can be administered in asolid or liquid form. Examples of solid dosage forms include but are notlimited to discrete units in capsules or tablets, as a powder orgranule, or present in a tablet conventionally formed by compressionmolding. Such compressed tablets may be prepared by compressing in asuitable machine the three or more agents and a pharmaceuticallyacceptable carrier. The molded tablets can be optionally coated orscored, having indicia inscribed thereon and can be so formulated as tocause immediate, substantially immediate, slow, controlled or extendedrelease of the opioid analgesics (such as oxycodone or hydrocodone)and/or the non-opioid analgesics (such as acetaminophen) and or theantihistamine (such as promethazine). Furthermore, dosage forms of theinvention can comprise acceptable carriers or salts known in the art,such as those described in the Handbook of Pharmaceutical Excipients,American Pharmaceutical Association (1986), incorporated by referenceherein in its entirety.

In one embodiment, one or more pharmaceutically active agents are mixedwith a pharmaceutical excipient to form a solid preformulationcomposition comprising a homogeneous mixture of compounds describedherein. When referring to these compositions as “homogeneous”, it ismeant that the agents are dispersed evenly throughout the composition sothat the composition can be subdivided into unit dosage forms such astablets or capsules. This solid preformulation composition can thensubdivided into unit dosage forms of the type described above comprisingfrom, for example, about 1.0 mg to about 15 mg of an opioid, such ashydrocodone or oxycodone or a pharmaceutically acceptable salt thereof.

The compositions can be formulated, in the case of capsules or tablets,to be swallowed whole, for example with water. The inclusion of theside-effect-reducing agent such as an antihistamine or antiemetic toabate common symptoms of nausea and vomiting are believed beneficial inthat promethazine or a salt thereof, or the like will eliminate orminimize the amount of discomfort. Adverse effects reduced or eliminatedinclude but are not limited to nausea, vomiting, other gastric upsets,skin rashes, allergic reactions such as swelling, difficulty breathing,closing of throat, abdominal pain, unusual bleeding or bruising, CNSsuppression and respiratory suppression.

Frequently, subjects taking opioids have adverse effects includingvomiting that can occur shortly after taking a first or subsequent dose.As a consequence, a portion of the opioid dose is subsequently lost,making it difficult to accurately gauge replacement dosages for thesubject, and for subjects outside of a hospital or clinic environment,there might not be any alternative form of pain medication readilyavailable. As a consequence, subjects experiencing gastric discomfortsuch as vomiting will lack the beneficial effects of the opioidanalgesic and experience the additional discomfort and enhanced painassociated with vomiting. This problem is solved by also administeringpromethazine or a salt thereof, which reduces side-effects.

The dosage forms described herein can be manufactured using processesthat are well known to those of skill in the art. For example, for themanufacture of bi-layered tablets, the agents can be dispersed uniformlyin one or more excipients, for example, using high shear granulation,low shear granulation, fluid bed granulation, or by blending for directcompression. Excipients include diluents, binders, disintegrants,dispersants, lubricants, glidants, stabilizers, surfactants andcolorants. Diluents, also termed “fillers”, can be used to increase thebulk of a tablet so that a practical size is provided for compression.Non-limiting examples of diluents include lactose, cellulose,microcrystalline cellulose, mannitol, dry starch, hydrolyzed starches,powdered sugar, talc, sodium chloride, silicon dioxide, titanium oxide,dicalcium phosphate dihydrate, calcium sulfate, calcium carbonate,alumina and kaolin. Binders can impart cohesive qualities to a tabletformulation and can be used to help a tablet remain intact aftercompression. Non-limiting examples of suitable binders include starch(including corn starch and pregelatinized starch), gelatin, sugars(e.g., glucose, dextrose, sucrose, lactose and sorbitol), celluloses,polyethylene glycol, waxes, natural and synthetic gums, e.g., acacia,tragacanth, sodium alginate, and synthetic polymers such aspolymethacrylates and polyvinylpyrrolidone. Lubricants can alsofacilitate tablet manufacture; non-limiting examples thereof includemagnesium stearate, calcium stearate, stearic acid, glyceryl behenate,and polyethylene glycol. Disintegrants can facilitate tabletdisintegration after administration, and non-limiting examples thereofinclude starches, alginic acid, crosslinked polymers such as, e.g.,crosslinked polyvinylpyrrolidone, croscarmellose sodium, potassium orsodium starch glycolate, clays, celluloses, starches, gums and the like.Non-limiting examples of suitable glidants include silicon dioxide, talcand the like. Stabilizers can inhibit or retard drug decompositionreactions, including oxidative reactions. Surfactants can also includeand can be anionic, cationic, amphoteric or nonionic. If desired, thetablets can also comprise nontoxic auxiliary substances such as pHbuffering agents, preservatives, e.g., antioxidants, wetting oremulsifying agents, solubilizing agents, coating agents, flavoringagents, and the like.

Controlled-release formulations can comprise one or more combination ofexcipients that slow the release of the agents by coating or temporarilybonding or decreasing their solubility of the active agents. Examples ofthese excipients include cellulose ethers such ashydroxypropylmethylcellulose (e.g., Methocel K4M) or silicifiedmicrocrystalline cellulose, polyvinylacetate-based excipients such as,e.g., Kollidon SR, and polymers and copolymers based on methacrylatesand methacrylic acid such as, e.g., Eudragit NE 30D. In one embodimentof the invention, the opioid analgesic or non-opioid agents (e.g.,hydrocodone or oxycodone or a salt thereof, and acetaminophen or a saltthereof) are formulated for extended or controlled-release while thepromethazine or a salt thereof is formulated for immediate release. Inanother embodiment, all agents are formulated for extended orcontrolled-release.

Immediate-release formulations can comprise one or more combination ofexcipients that allow for a rapid release of a pharmaceutically activeagent (such as from 1 minute to 1 hour after administration), such as ananti-emetic or an antihistamine. In one embodiment an immediate releaseexcipient can be microcrystalline cellulose, sodium carboxymethylcellulose, sodium starch glycolate, corn starch, colloidal silica,Sodium Laurel Sulphate, Magnesium Stearate, Prosolve SMCC (HD90),croscarmellose Sodium, Crospovidone NF, Avicel PH200, and combinationsof such excipients.

Pharmaceutical carriers or vehicles suitable for administration of thecompounds provided herein include all such carriers known to thoseskilled in the art to be suitable for the particular mode ofadministration. In addition, the compositions can one or more componentsthat do not impair the desired action, or with components thatsupplement the desired action, or have another action. As noted above,the compositions can comprise additional (e.g., a fourth, fifth, sixth,etc.) additional active agents.

In one embodiment, the compositions comprise three or morepharmaceutically active agents wherein at least one active agent isformulated in an immediate release form. In this embodiment theimmediate-release form can be included in an amount that is effective toshorten the time to its maximum concentration in the blood. By way ofexample, certain immediate-release pharmaceutical preparations aretaught in United States Patent Publication US 2005/0147710A1 entitled,“Powder Compaction and Enrobing” which is incorporated herein in itsentirety by reference.

In a further embodiment, a component of an immediate-release form orlayer is a component that reduces abates or eliminates and/or suppressesan adverse effect associated with one or more opioid analgesics.

For example, the immediate-release active can be an antihistamine or anantiemetic, which reduces, abates or eliminates an adverse effectassociated with opioid and/or non-opioid analgesics described herein.

In a further embodiment, all or less than the entire amount of theantiemetic or antihistamine agent is formulated in immediate-releaseform, as described herein.

A variety of known methods and materials may be used to bring about theimmediate release. For instance, placement of the agent along anexterior of a tablet (e.g., coating the exterior or formulating theouter layer with the agent) and/or combined with forming a tablet bycompressing the powder using low compaction can produceimmediate-release of the agent from the composition.

In a specific embodiment, an effective amount of the promethazine or asalt thereof in immediate-release form may be coated onto a substrate.For example, where the extended release of one or more analgesics from aformulation is due to a controlled-release coating, an immediate-releaselayer comprising promethazine or a salt thereof can overcoat thecontrolled-release coating. In another example, an immediate-releaselayer can be coated onto the surface of a substrate wherein an opioid, anon-opioid agent, a barbiturate, or a stimulant is incorporated in acontrolled release matrix. Where a plurality of controlled-releasesubstrates (e.g., multiparticulate systems including pellets, spheres,beads and the like) are incorporated into a hard gelatin capsule, aside-effect-reducing compound can be incorporated into the gelatincapsule via inclusion of an amount of immediate-release promethazine ora salt thereof, as a powder or granulate within the capsule.Alternatively, the gelatin capsule itself can be coated with animmediate-release layer of promethazine. One skilled in the artrecognizes still other alternative means of incorporating an immediaterelease side-effect-reducing compound into the unit dose. By includingan effective amount of immediate-release side-effect-reducing compoundin the unit dose, the experience of adverse effects including nausea,vomiting, other gastric upsets, skin rashes, allergic reactions such asswelling, difficulty breathing, closing of throat, abdominal pain,unusual bleeding or bruising, skin rashes, sedation, CNS depression, orrespiratory depression in subjects can be significantly reduced.

In one embodiment, the composition comprises three or more active agentswherein at least one active agent is in controlled-release form. Thecontrolled-release form can be in an amount that is effective to protectthe agent from rapid elimination from the body. Certain preparationsrelating to the controlled release of a pharmaceutical are taught inUnited States Patent Publication US 2005/0147710A1 entitled, “PowderCompaction and Enrobing” which is incorporated herein in its entirety byreference. Examples of time release coated beads are disclosed in U.S.Application Publication No. 20080131517.

In a further embodiment, at least one pharmaceutically active agent in acontrolled-release form is an opioid analgesic agent. In one embodimentof the invention, compositions comprise one or more carriers thatprotect the agents against rapid elimination from the body, such astime-release formulations or coatings. Such carriers includecontrolled-release formulations, including, for example,microencapsulated delivery systems. The active agents can be included inthe pharmaceutically acceptable carrier in amounts sufficient to treat asubject's pain, with reduced adverse effects.

In certain embodiments the compositions are in oral-dosage form andcomprise a matrix that includes, for example, a controlled-releasematerial and an opioid or non-opioid analgesic. In certain embodiments,the matrix is compressible into a tablet and can be optionallyovercoated with a coating that can control the release of the opioid ornon-opioid analgesic from the composition. In this embodiment bloodlevels of analgesics are maintained within a therapeutic range over anextended period of time. In certain alternate embodiments, the matrix isencapsulated.

Tablets or capsules containing a composition described herein can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or capsule cancontain an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer that serves to resist disintegration inthe stomach and permit the inner component to pass intact into theduodenum or to be controlled in release. For controlled extendedrelease, the capsule can also have micro drilled holes.

A coating comprising a side-effect-reducing compound, in immediaterelease form, can be added to the outside of a controlled-release tabletcore to produce a final dosage form. Such a coating can be prepared byadmixing a compound like promethazine with polyvinylpyrrolidone (PVP)29/32 or hydroxypropyl methylcellulose (HPMC) and water/isopropylalcohol and triethyl acetate. Such an immediate-release coating can bespray coated onto the tablet cores. The immediate-release coating canalso be applied using a press-coating process with a blend consisting of80% by weight promethazine and 20% by weight of lactose andhydroxypropyl methylcellulose type 2910. Press-coating techniques areknown in the art and are described in U.S. Pat. No. 6,372,254, which isherein incorporated by reference in its entirety.

The immediate-release or controlled-release dosage forms describedherein can also take the form of a bi-layered tablet, which comprises afirst layer and a second layer. The first layer comprises a first drugthat is an analgesic, antitussive, antihistamine, and antiemetic. Thesecond layer comprises a second drug that is an analgesic, antitussive,antihistamine, and antiemetic. The second drug is the same as ordifferent from the first drug. The bi-layered tablet can provide aplasma concentration within the therapeutic range of the second drugover a period which is coextensive with at least about 70% of the period(e.g., 12 hours) within which the bi-layered tablet provides a plasmaconcentration within the therapeutic range of the first drug.

In a further embodiment of the bi-layered tablet, one layer is animmediate release layer and the other layer is a controlled-releaselayer. In one example a bi-layered is formulated using the methodsdisclosed in U.S. Pat. No. 4,820,522, which is herein incorporated byreference in its entirety.

In one embodiment of the bi-layered tablet described herein, both layerscan comprise an opioid analgesic, a non-opioid analgesic and a compoundto reduce or suppress adverse effects.

In a further embodiment of the bi-layered tablet described herein, theimmediate-release layer comprises promethazine or a salt thereof and thecontrolled release layer comprises hydrocodone or oxycodone or apharmaceutically acceptable salt thereof. In one embodiment theimmediate or controlled release layer can further comprise acetaminophenor naproxen or a salt thereof.

In one embodiment of the multi-layered tablet, the second drug can havea plasma half-life that differs from the plasma half-life of the firstdrug by at least about 2 hours.

In another embodiment, an effective amount of the antiemetic agent orantihistamine in an immediate-release form may be coated onto asubstrate. For example, where the one or more opioid analgesics and oneor more stimulant are components of a controlled-release formulation, animmediate-release layer comprising the antiemetic agent or antihistaminecan overcoat the controlled-release formulation.

In another embodiment, the immediate-release layer can be coated ontothe surface of a substrate having a controlled release matrix. Where aplurality of controlled-release substrates comprising an effective unitdose of a pharmaceutically active agent (e.g., multiparticulate systemsincluding pellets, spheres, beads and the like) are incorporated into ahard gelatin capsule, another agent can be incorporated into the gelatincapsule via inclusion of an amount of immediate-release agent as apowder or granulate within the capsule. Alternatively, the gelatincapsule itself can be coated with an immediate-release layer. Oneskilled in the art recognizes still other alternative means ofincorporating the immediate release side-effect-reducing compound intothe unit dose. Therefore, in one embodiment, by including an effectiveamount of an antiemetic agent or antihistamine (and optionally includinga stimulant) in the unit dose, the subject is prepared for the eventualand subsequent release of one or more opioid analgesic in thecontrolled-release layer, where the antiemetic agent or antihistaminereduces the incidence of or intensity of adverse effects associated withan opioid agent including but not limited to nausea, vomiting, othergastric upsets, skin rashes, allergic reactions such as swelling,difficulty breathing, closing of throat, abdominal pain, unusualbleeding or bruising, skin rashes, sedation, CNS depression, orrespiratory depression in subjects can be significantly reduced.

The immediate-release or controlled-release dosage forms describedherein can also take the form of a bi-layered tablet, which can comprisean immediate-release layer and a controlled-release layer. In oneembodiment the immediate release layer comprises an antiemetic agent orantihistamine, and optionally a stimulant or a non-opioid analgesic, orboth. In one embodiment, the first layer can comprise one, two, three ormore active agents. The controlled release layer can comprise an opioidanalgesic or non-opioid analgesic or stimulant. Such classes of activeagents are described herein above.

The immediate-release or controlled release dosage forms describedherein can also take the form of pharmaceutical particles manufacturedby a variety of methods, including but not limited to high-pressurehomogenization, wet or dry ball milling, or small particle precipitation(nano spray). Other methods to make a suitable powder formulation arethe preparation of a solution of active ingredients and excipients,followed by precipitation, filtration, and pulverization, or followed byremoval of the solvent by freeze-drying, followed by pulverization ofthe powder to the desired particle size.

In one embodiment the particles have a final size of 3-1000 μm, such asat most 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100,150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800,850, 900, 950, 1000 μm. In another embodiment the pharmaceuticalparticles have a final size of 10-500 μm. In one embodiment thepharmaceutical particles have a final size of 50-600 μm. In anotherembodiment the pharmaceutical particles have a final size of 100-800 μm.These dosage forms can include immediate-release particles incombination with controlled-release particles in a ratio sufficientuseful for delivering the desired dosages of active agents. In analternative embodiment, a dosage unit can be divided into or exclusivelyincluded into both immediate release and controlled release particles.

In a further embodiment the dosage form can be an effervescent dosageform. Effervescent means that the dosage form, when mixed with liquid,including water and saliva, evolves a gas. Some effervescent agents (oreffervescent couple) evolve gas by means of a chemical reaction whichtakes place upon exposure of the effervescent disintegration agent towater and/or to saliva in the mouth. This reaction can be the result ofthe reaction of a soluble acid source and an alkali monocarbonate orcarbonate source. The reaction of these two general compounds producescarbon dioxide gas upon contact with water or saliva. An effervescentcouple (or the individual acid and base separately) can be coated with asolvent protective or enteric coating to prevent premature reaction.Such a couple can also be mixed with previously lyophilized particles(such as one or more pharmaceutically active agents coated with asolvent protective or enteric coating. The acid sources may be any whichare safe for human consumption and may generally include food acids,acid and hydrite antacids such as, for example: citric, tartaric,amalic, fumeric, adipic, and succinics. Carbonate sources include drysolid carbonate and bicarbonate salt such as, for example, sodiumbicarbonate, sodium carbonate, potassium bicarbonate and potassiumcarbonate, magnesium carbonate and the like. Reactants which evolveoxygen or other gasses and which are safe for human consumption are alsoincluded. In one embodiment citric acid and sodium bicarbonate is used.

In another embodiment the dosage form can be in a candy form (e.g.,matrix), such as a lollipop or lozenge. In one embodiment one or morepharmaceutically active agents is dispersed within a candy matrix. Inone embodiment the candy matrix comprises one or more sugars (such asdextrose or sucrose). In another embodiment the candy matrix is asugar-free matrix. The choice of a particular candy matrix is subject towide variation. Conventional sweeteners such as sucrose may be utilized,or sugar alcohols suitable for use with diabetic patients, such assorbitol or mannitol might be employed. Other sweeteners, such as theaspartanes, can also be easily incorporated into a composition inaccordance with compositions described herein. The candy base may bevery soft and fast dissolving, or may be hard and slower dissolving.Various forms will have advantages in different situations.

A containing candy mass comprising at least one pharmaceutically activeagent can be orally administered to a subject in need thereof so thatthe agent will be released into the subject's mouth as the candy massdissolves. The drug rapidly enters the subject bloodstream, andimportantly, the blood in the veins draining from the mouth and thepharyngeal and esophageal areas passes through a substantial portion ofthe body (so that the drug can be absorbed) before the blood passesthrough the liver (where the drug may be inactivated). A subject in needthereof can include a human adult or child in pain, such as a child insickle cell crisis, a child undergoing bone marrow transplant or alumbar puncture procedure, a child with cancer (e.g., metastasic cancer,leukemia or lymphoma).

In some embodiments of the invention the candy matrix (lollipop orlozenge) comprises a composition that lacks a stimulant. In oneembodiment said formulation may have a sedative effect in addition toproviding pain relief to a subject in need thereof. In some otherembodiments the candy matrix (lollipop or lozenge) comprises acomposition that comprises a stimulant. In these embodiments thecomposition provides an anti-sedative effect in addition to providingpain relief to a subject in need thereof.

In one embodiment a candy mass is prepared that comprises one or morelayers which may comprise different pharmaceutically active agents andor rates of dissolution. In one embodiment a multilayer candy mass (suchas a lollipop) comprises an outer layer with a concentration of one ormore pharmaceutically active agents differing from that of one or moreinner layers. Such a drug delivery system has a variety of applications.By way of example, it may be desirable to quickly get a predetermineddose of a first pharmaceutically active agent into the bloodstream toobtain a desired effect and then use a different inner layer to deliverone or more other agents.

The choices of matrix and the concentration of the drug in the matrixcan be important factors with respect to the rate of drug uptake. Amatrix that dissolves quickly can deliver drug into the patient's mouthfor absorption more quickly than a matrix that is slow to dissolve.Similarly, a candy matrix that contains one or more pharmaceuticallyactive agents in a high concentration can release more of the one ormore pharmaceutically active agents in a given period of time than acandy having a low concentration. In one embodiment a candy matrix suchas one disclosed in U.S. Pat. No. 4,671,953 or US Application2004/0213828 (which are herein incorporated by reference in theirentirety) is used to deliver the pharmaceutically active agentsdisclosed herein.

The immediate-release or extended release dosage forms described hereincan also take the form of pharmaceutical particles manufactured by avariety of methods, including but not limited to high-pressurehomogenization, wet or dry ball milling, or small particle precipitation(e.g., nGimat's NanoSpray). Other methods useful to make a suitablepowder formulation are the preparation of a solution of activeingredients and excipients, followed by precipitation, filtration, andpulverization, or followed by removal of the solvent by freeze-drying,followed by pulverization of the powder to the desired particle size. Inone embodiment the pharmaceutical particles have a final size of 3-1000μm, such as at most 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80,90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700,750, 800, 850, 900, 950, 1000 μm. In another embodiment thepharmaceutical particles have a final size of 10-500 μm. In anotherembodiment the pharmaceutical particles have a final size of 50-600 μm.In another embodiment the pharmaceutical particles have a final size of100-800 μm. These dosage forms can include immediate-release particlesin combination with controlled-release particles in a ratio sufficientuseful for delivering the desired dosages of active agents. For example,the immediate-release particles can comprise about 12.5 mg ofpromethazine or a salt thereof, and the controlled-release particles cancomprise about 7.5 mg of hydrocodone or oxycodone or a salt thereof, andabout 325 mg of acetaminophen or a salt thereof.

In another embodiment, the agents are released from a multi-layeredtablet that comprises at least a first layer, a second layer and a thirdlayer. Wherein, the layers containing a pharmaceutically active agentcan be optionally separated by one or more layers of inert materials. Inone embodiment the layers containing a pharmaceutically active agenthave similar rates of release, e.g., all are immediate release or allare controlled-release. In an alternative embodiment the layers havedifferent rates of release. In this embodiment at least one layer is animmediate release layer and at least one layer is a controlled releaselayer. For example in one embodiment the multilayer tablet comprises atleast three layers, each of which contains a different agent, such as:layer one contains promethazine or a salt thereof; layer two compriseshydrocodone or oxycodone or a salt thereof; and layer three comprisesacetaminophen or a salt thereof. In this embodiment the promethazinelayer may be immediate-release, while the other two layers may becontrolled-release.

Transdermal Dosage Forms

In another embodiment, the invention relates to a method of use and asystem for the transdermal delivery of one or more pharmaceuticallyactive agents into a subject. In one embodiment a portion of the skin ofa subject is sealed with a thin, film layer of a base material toocclude the skin and transport a desired dosage of at least onepharmaceutically active agent across the a layer, which can be from arate-controlling system in contact with the thin layer. Therate-controlling system can be a thin rate-controlling membraneinterposed between one or more agents and the thin layer. In anotherembodiment a reservoir delivers at least one pharmaceutically activeagent to the layer for delivery into a subject. In some embodiments thepharmaceutically active agents to be delivered are: an opioid analgesic,a non-opioid analgesic and an antihistamine; or pharmaceuticallyacceptable salts, solvates, or prodrugs thereof; one or morepharmaceutically acceptable excipients or carriers.

In one embodiment, the rate-controlling system or reservoir comprises atleast one pharmaceutically active agent to be delivered, is dispersed ina base material and contained within a container system. In oneembodiment at least one pharmaceutically active agent is dissolved inthe base material. In another embodiment at least one pharmaceuticallyactive agent is uniformly dispersed in the base material. In anotherembodiment, the rate-controlling system or reservoir comprisesmicroparticles of at least one pharmaceutically active agent to bedelivered suspended in a base material and contained within a containersystem. In one embodiment the base material is a viscous material. Thecontainer system may comprise a macroporous, non-rate-controlling facemembrane with an impervious backing to form a pool or patch-like systemof desired face membrane area with the face of the membrane placed overand in contact with the thin, occluding, viscous layer on the skin. Thethin viscous layer may be coated or placed on the skin repeatedly, andthe patch system placed on top of the thin, viscous layer or the viscouslayer formed in situ by exudation through the membrane face when thepatch or pool system is placed in position on the skin. In oneembodiment the patch or pool container system generally is retained in atransdermal position by the use of a peripheral adhesive layer about thepatch or pool. In one embodiment, the face or transport area of themembrane is covered prior to use by a removable cover such as a peelablestrip of impervious sheet material. In another embodiment, microcapsulescontaining a drug for delivery may be suspended in a viscous basematerial, and the composition then spread as a layer over the skin ofthe user with or without a covering material.

In other embodiments U.S. Pat. Nos. 4,906,463; 4,588,580; 4,685,911,4,626,539, 4,834,978 and 5,635,204 disclose useful transdermal patcheswhich may be used for the practice methods and compositions describedherein, which are herein incorporated by reference in their entirety.

In one embodiment the compositions are administered to a subject via atransdermal patch.

Suppository Dosage Form

In another embodiment, the compositions are in the form of asuppository. In one embodiment the suppository is useful for vaginal orrectal administration. In some embodiments the suppository iseffervescent.

In some embodiments the suppository base material contains hydrophobicor hydrophilic media, each of which can melt at body temperature. In oneembodiment the suppository base material used can be cocoa butter orsimilar material. In another embodiment the suppository base materialcan be a moist polymer is then mixed with the one or morepharmaceutically active agents and compressed into the desired form. Inone embodiment at least one pharmaceutically active agent is dissolvedin the suppository base material. In another embodiment at least onepharmaceutically active agent is uniformly dispersed in the suppositorybase material. In another embodiment, the suppository base materialcomprises microparticles of at least one pharmaceutically active agentto be delivered suspended in the suppository base material. In someembodiments (such as vaginal suppositories) the suppository iseffervescent. In some embodiments the effervescing properties areimparted for the purpose of enhancing the rapid disintegrationproperties of the suppository.

In other embodiments U.S. Pat. Nos. 4,265,875 and 4,853,211 discloseuseful suppositories which may be used for the practice of methods andcompositions described herein, which are herein incorporated byreference in their entirety.

Abuse Safeguard Dosage Forms

Adverse-Effect Agents

In one embodiment, the present compositions can safeguard against abuseof the opioid analgesic agent. For example, a composition disclosedherein can further comprise an effective amount of an adverse-effectagent or antagonist agent that reduces or eliminates one or more of: (1)the capacity of the opioid analgesic agent to produce the kind ofphysical dependence in which withdrawal causes sufficient distress tobring about drug-seeking behavior; (2) the ability to suppresswithdrawal symptoms caused by withdrawal from the opioid analgesicagent; and (3) the induction of euphoria. Useful adverse-effect agentsinclude, but are not limited to, opioid antagonists. When there is apotential for an overdose, then an antidote of the opioid analgesicagent can be used as the adverse-effect agent.

The phrase “adverse-effect agent” is also meant to encompass allpharmaceutically acceptable salts of the adverse-effect agent.

Opioid antagonists that can be used as an adverse-effect agent include,but are not limited to, naloxone, naltrexone, nalmefene, cyclazacine,levallorphan, or a salt thereof, and mixtures thereof. In certainembodiments, the opioid antagonist is naloxone, naltrexone or apharmaceutically acceptable salt thereof.

In some embodiments, the opioid agent and the opioid antagonist arepresent in a ratio of opioid antagonist to opioid agent (analgesic)which is analgesically effective when the combination is administeredorally, but which is aversive in a physically dependent subject. In thismanner, the combination product (antagonist/agonist) could in essence betherapeutic to one population (patients in pain), while beingunacceptable (aversive) in a different population (e.g., physicallydependent subjects) when orally administered at the same dose or at ahigher dose than the usually prescribed dosage, e.g., about 2-3 timesthe usually prescribed dose of the opioid. Thus, the oral dosage formwould have less potential for parenteral as well as oral abuse. In oneembodiment where the opioid is hydrocodone or oxycodone or a saltthereof and the antagonist is naltrexone or a salt thereof, the ratio ofnaltrexone or a salt thereof to hydrocodone or a salt thereof is fromabout 0.02-0.35:1 by weight, and in some embodiments from about0.05-0.2:1 by weight. In one embodiment the ratio of naltrexone or asalt thereof is in an amount from about 0.5 to about 4 mg per 15 mg ofhydrocodone or a salt thereof. In another embodiment the ratio ofnaltrexone or a salt thereof is in an amount from about 0.75 mg to about3 mg per 15 mg hydrocodone or a salt thereof. In another example wherethe opioid antagonist is naltrexone or a salt thereof and the opioidagent is hydromorphone or a salt thereof, the ratio of naltrexone or asalt thereof to hydromorphone or a salt thereof can be from about 0.14:1to about 1.19:1, or from about 0.222:1 to about 0.889:1. In anotherexample where the opioid antagonist is naltrexone or a salt thereof andthe opioid agent is oxycodone or a salt thereof, the ratio of naltrexoneor a salt thereof to oxycodone or a salt thereof is about 0.03:1 toabout 0.3:1, or from about 0.056:1 to about 0.222:1.

In one embodiment, the opioid is hydrocodone, hydromorphone, oxycodone,fentanyl, or a pharmaceutically acceptable salt thereof.

In some embodiments, an opioid antagonist is administered in an amount(i) which does not cause a reduction in the level of analgesia elicitedfrom the dosage form upon oral administration to a non-therapeutic leveland (ii) which provides at least a mildly negative, “aversive”experience in physically dependent subjects (e.g., precipitatedabstinence syndrome) when the subjects attempt to take at least twicethe usually prescribed dose at a time (and often 2-3 times that dose ormore), as compared to a comparable dose of the opioid without the opioidantagonist present. In certain embodiments, an amount of naltrexone or asalt thereof is included in the oral dosage form and is less positivelyreinforcing (e.g., less “liked”) to a non-physically dependent opioidaddict than a comparable oral dosage form without the antagonistincluded. In one embodiment the composition provides effective analgesiawhen orally administered.

In some embodiments the oral dosage form can be administered on atwice-a-day or a once-a-day basis.

The composition can be formulated as a controlled oral formulation inany suitable tablet, coated tablet or multiparticulate formulation knownto those skilled in the art. The controlled release dosage form canoptionally include a carrier which is incorporated into a matrix or canbe applied as a controlled release coating.

In embodiments in which the opioid analgesic is hydrocodone (or apharmaceutically acceptable salt thereof), the extended release oraldosage forms may include analgesic doses from about 4 mg to about 60 mgof hydrocodone or a salt thereof per dosage unit. In a controlledrelease oral dosage forms where hydromorphone or a salt thereof is thetherapeutically active opioid, it can be included in an amount fromabout 2 mg to about 64 mg hydromorphone hydrochloride. In yet anotherembodiment, the opioid analgesic is oxycodone and the controlled releaseoral dosage forms include from about 2.5 mg to about 800 mg oxycodoneHCL. Alternatively, the dosage form may contain molar equivalent amountsof other salts of the opioids useful in compositions described herein.

In other embodiments U.S. Pat. Nos. 6,228,863; 6,475,494; 7,201,920; andU.S. Pat. Nos. 7,172,767, 7,201,920 disclose useful opioid agent/opioidantagonist formulations which can be used for the methods andcompositions described herein, which are herein incorporated byreference in their entirety.

In another embodiment, one or more non-opioid analgesic agents, inaddition to the opioid antagonist, can be included in the dosage form.Such non-opioid drugs can provide additional analgesia, and include, forexample, aspirin; acetaminophen; non-steroidal anti-inflammatory drugs(“NSAIDS”), e.g., ibuprofen, naproxen, ketoprofen, etc.;N-methyl-D-aspartate (NMDA) receptor antagonists, e.g., a morphinan suchas dextromethorphan or dextrorphan, or ketamine; cycooxygenase-IIinhibitors (“COX-II inhibitors”); and/or glycine receptor antagonists.

Abuse Deterrent Agents

In another embodiment the compositions comprising an opioid analgesicsafeguards against abuse by further comprising one or more abusedeterrent agents. The choice of which abuse deterrent agent to includein a composition can be varied depending on the route of administrationand intended method of treatment. For example different abuse deterrentagents can be used in conjunction with same pharmaceutically activeagents depending on if they are formulated as an oral dosage form or atransdermal dosage form. Similarly, compositions intended to treat acancer associated pain in a subject can comprise a different abusedeterrent agent than a composition intended to treat headache associatedpain in a subject.

In one embodiment the abuse deterrent agent is formulated as agel-forming agent, and optionally comprises one or more mucous membraneirritants or nasal passageway tissue irritants. In another embodiment,the compositions described herein include a composition comprising ananalgesic, one or more gel-forming agents and one or more emetics asdescribed herein. In another embodiment, the compositions comprise anopioid analgesic, one or more mucous membrane irritants or nasalpassageway tissue irritants and one or more emetics as described herein.In one particular embodiment, the compositions comprise an analgesic,one or more gel-forming agents, one or more mucous membrane irritantsand/or nasal passageway tissue irritants, and one or more emetics.

Suitable gel-forming agents include compounds that, upon contact with asolvent (e.g., water), absorb the solvent and swell, thereby forming aviscous or semi-viscous substance that significantly reduces and/orminimizes the amount of free solvent which can contain an amount ofsolubilized drug, and which can be drawn into a syringe. The gel canalso reduce the overall amount of drug extractable with the solvent byentrapping the drug in a gel matrix. In one embodiment, typicalgel-forming agents include pharmaceutically acceptable polymers,typically hydrophilic polymers, such as hydrogels.

In some embodiments, the polymers exhibit a high degree of viscosityupon contact with a suitable solvent. The high viscosity can enhance theformation of highly viscous gels when attempts are made by an abuser tocrush and dissolve the contents of a dosage form in an aqueous vehicleand inject it intravenously.

More specifically, in certain embodiments the polymeric materialdescribed herein provides viscosity to the dosage form when it istampered. In such embodiments, when an abuser crushes and dissolves thedosage form in a solvent (e.g., water or saline), a viscous orsemi-viscous gel is formed. The increase in the viscosity of thesolution discourages the abuser from injecting the gel intravenously orintramuscularly by preventing the abuser from transferring sufficientamounts of the solution to a syringe to cause a desired “high” onceinjected.

Suitable polymers include one or more pharmaceutically acceptablepolymers selected from any pharmaceutical polymer that will undergo anincrease in viscosity upon contact with a solvent. Polymers can includepolyethylene oxide, polyvinyl alcohol, hydroxypropyl methyl celluloseand carbomers.

In another embodiment the compositions comprise an abuse deterrent agentthat is a mucous membrane irritant or nasal passageway tissue irritant,or both. These irritants are designed to deter abuse via the improperadministration of a dosage form comprising an opioid (e.g., crushing andsnorting). In one embodiment, suitable mucous membrane irritants ornasal passageway tissue irritants include compounds that are generallyconsidered pharmaceutically inert, yet can induce irritation. Suchcompounds include, but are not limited to surfactants. In oneembodiment, suitable surfactants include sodium lauryl sulfate,poloxamer, sorbitan monoesters and glyceryl monooleates. Other suitablecompounds are believed to be within the knowledge of a practitionerskilled in the relevant art, and can be found in the Handbook ofPharmaceutical Excipients, 4th Ed. (2003), the entire content of whichis hereby incorporated by reference.

In one embodiment the irritant can be present in amount of from 1 to 10percent by weight on a solid basis, such as from about 1 to 5 percent byweight on a solid basis. In another embodiment, the amount of irritantcan be present in an amount from 1 to 3 percent by weight.

In another embodiment, the irritant can deter abuse of a dosage formwhen a potential abuser tampers with a dosage form described herein.Specifically, in such embodiments, when an abuser crushes the dosageform, the irritant is exposed. The irritant discourages inhalation ofthe crushed dosage form by inducing pain and/or irritation of theabuser's mucous membrane and/or nasal passageway tissue. In oneembodiment, the irritant discourages inhalation (e.g., via snortingthrough the nose) by inducing pain and/or irritation of the abuser'snasal passageway tissue.

In one embodiment, the compositions described herein comprise one ormore mucous membrane irritants that cause irritation of mucous membraneslocated anywhere on or in the body, including membranes of the mouth,eyes and intestinal tract. Such compositions can deter abuse via oral,intra-ocular or rectal or vaginal routes.

In another embodiment the compositions comprise an abuse deterrent agentthat is an emetic or emesis inducing agent. In one embodiment the emeticcan be a pharmaceutically acceptable inert excipient that only inducesemesis after a certain threshold amount is ingested. In anotherembodiment, the emetic can be a pharmaceutically active emetic.

In one embodiment, the amount of emetic present in the compositionsdescribed herein can be tied directly to the amount of drug in thecomposition. Thus, by controlling the quantity of the emetic compound inthe composition, emesis can be avoided if normal prescription directionsare followed. However, if an overdosage occurs by ingesting more than aprescribed quantity of a drug in a composition described herein, theamount of ingested emetic can exceed the threshold amount necessary toinduce emesis.

In some embodiments, the threshold amount of emetic for inducing emesiscan be reached when the normal prescription directions areinappropriately increased by factors of 2, 3, 4, 5, 6, 7, or 8 times, ormore. Thus, in some embodiments, the amount of emetic present in acomposition described herein is an amount such that the amount of emeticingested does not exceed the threshold amount necessary for inducingemesis until a subject ingests 2, 3, 4, 5, 6, 7, or 8 or more times theamount of drug normally prescribed. In some embodiments, emesis canpreclude death or serious illness in the subject.

In one embodiment, the emetic is zinc sulfate. Zinc sulfate is anexcipient, which can induce emesis when more than about 0.6 to 2.0 gm isingested, typically more than about 0.6 gm, or about 5 to 25 percent byweight on a solid basis, more typically about 5 to 10 percent by weight.Accordingly, compositions described herein can be easily designed toinduce emesis if a prescribed dosage is exceeded and/or if prescriptiondirections are not followed for dosage forms containing a compositiondescribed herein. Typically, suitable embodiments include less thanabout 0.6 to 2.0 gm of zinc sulfate.

For example a dosage form can induce emesis only after a pre-determinednumber of dosage forms are ingested (such as 4, 5, 6 or more), in thiscase the amount of zinc sulfate in each dosage form should not exceedabout 0.19 gm. Thus, if three dosage forms are ingested, the amount ofemetic can be 0.57 gm, which is less than a typical threshold amount ofthe particular emetic. However, if a fourth dosage form having 0.19 gm.of zinc sulfate is ingested, the amount of emetic exceeds the thresholdamount, and emesis is induced.

In another embodiment the compositions comprise an effective amount ofan abuse deterrent agent that induces flushing, (i.e. redness of theskin, including redness of the skin of one or more of the face, neck,chest, back and trunk and legs) and/or itching and/or discomfort and/ortemporary pain (a flushing/pain inducing agent or flushing inducingagent), and/or generalized pruritic, and/or intense warmth, and/orchills when administered at or in excess of a threshold amount.

With respect to flushing, discomfort and pain inducing agents, athreshold amount is an amount below which one or more adverse effects isabsent or below which a subject may experience a beneficial effect.

In one embodiment, the flushing agent or itching agent or pain-inducingagent is a drug. In certain embodiments, the drug is obtainable “overthe counter” and in certain embodiments, the “over the counter” drug isa vitamin. In yet another embodiment, the vitamin is niacin. In anotherembodiment, the present invention includes vitamin.

Accordingly, in one embodiment the amount of flushing, itching, or paininducing agent present in a composition described herein can be tieddirectly to the amount of drug in the composition. Thus, by controllingthe quantity of the flushing, itching, or pain inducing agent in thecomposition, flushing, itching, or pain can be avoided if normalprescription directions are followed. However, if an overdosage occursby ingesting more than a prescribed quantity of a drug in a compositiondescribed herein (e.g., by ingesting more than the prescribed dose), thetotal amount of flushing, itching, or pain inducing agent can, incertain embodiments, exceed the threshold amount necessary to induceflushing, itching, or pain thereby inducing flushing, itching, or pain.

In one embodiment, compositions and methods described herein includesabout 10 mg to about 500 mg of the flushing, itching, or pain inducingagent. In yet another embodiment, a composition comprises about 15 mg toabout 150 mg of a flushing, itching, or pain agent. In anotherembodiment, a composition comprises 15, 30, 45, 60, 75, 90 or 105 mg ofa flushing, itching, or pain inducing agent. In one embodiment,compositions and methods described herein includes a flushing, itching,or pain inducing agent in an amount of about 1% to 25%, typically about3% to 15%, more typically about 1%, 3%, 6%, 9%, 12%, 15% or 20% byweight, including or excluding the weight of any analgesic and/or otherdrug susceptible to abuse.

In some embodiments of dosage forms having a controlled release layer orformulation, the amount of flushing inducing agent (and in otherembodiments, the amount of any abuse deterrent component or opioidantagonist described herein), can exceed the threshold amount present inan immediate release form. This is because in controlled releaseformulations, the amount of drug which is susceptible to abuse istypically higher than in an immediate release formulation and theflushing inducing agent (or other abuse deterrent component) becomesbioavailable at a slower rate than the immediate release form. Thus, theamount of abuse deterrent component which is bioavailable typically alsoremains below the amount sufficient to cause an abuse deterrent effect.However, if the dosage form is tampered with (e.g., ground, chewed orcrushed), a large portion of the abuse deterrent component becomesimmediately bioavailable, thus inducing one or more abuse deterrenteffects.

Examples of abuse deterrent agents that can be used in compositionsdescribed herein are disclosed in US Patent Application Nos:US20060177380A1; US20060110327A1; and US20070231268A1, which are hereinincorporated by reference in its entirety.

Abuse Deterrence Via Chemical Modification of Active Agents

In another embodiment the compositions comprise an opioid agent that isconjugated to a chemical moiety. The chemical moiety can be any chemicalsubstance that can be attached to the opioid agent in a manner thatrenders it pharmacologically inactive. Analgesics and stimulants producetheir pharmacological effects through binding to specific receptors oruptake proteins. The attachment of certain chemical moieties cantherefore prevent the active substance from binding its receptor(s) orrecognition site on its uptake protein. Further, without being bound bytheory, the covalent modification is believed to prevent thepharmacological effect by preventing the drug from crossing theblood-brain barrier. The attachment of the chemical moiety to the opioidagent can also prevent or substantially delay the absorption of thecompound, particularly when the compound is delivered by routes otherthan oral administration.

In one embodiment of the invention, the chemical moiety is attached tothe opioid agent in a manner in which it is not readily released byconditions found in the mouth (saliva), the intranasal cavity, thesurface of the lungs, or in the serum. Extreme acid conditionsencountered in the stomach are not present elsewhere in humans.Therefore, any acid dependent release mechanism will occur only afteroral administration. Although, degradative enzymes are present in theaforementioned environments, they are not generally present in the highconcentrations found in the intestinal tract. Thus, release of theopioid agent by enzymatic cleavage will not occur rapidly when the novelcompounds are administered by routes other than oral delivery.

In another embodiment of the invention, the opioid agent is attached toa polymer of serine (or other amino acid containing a hydroxyl sidechain e.g. threonine, tyrosine) via side chain hydroxyl groups.Alternatively, attachment is to a polymer of glutamic acid through thecarboxyl group of the delta carbon of glutamic acid. The resulting ester(carbonate) linkages can be hydrolysed by lipases (esterases)encountered in the small intestine. Esterases are not present at highlevels in saliva or on the mucosal surfaces of the nasal cavity, lungs,or oral cavity. Thus, opioid agents attached to polyglutamic acid bythis method would not be rapidly released by saliva or when deliveredintranasally or by inhalation.

In another embodiment of the invention, the opioid agent is attached toan oligopeptide, which can consist of between one and five amino acids.In a further embodiment of the invention the amino acids are aheterogenous mixture of the twenty naturally occurring amino acids.Hydrophilic amino acids will tend to prevent passive absorption of theanalgesic peptide conjugate through nasal membranes. In one embodimentof the invention that hydrophilic amino acids be included in theoligopeptide. In another embodiment of the invention that lipophilicamino acids be attached closer to the analgesic for optimum stability.Both lipophilic and hydrophilic properties (i.e., amphiphilic) can besatisfied with between three and five amino acids. In a furtherembodiment of the invention, the oligopeptide that is attached to theanalgesic can be an amphiphilic tripeptide.

Amphiphilic amino acids/oligopeptides may contain (i) hydrophobic aminoacids, located in positions next to the active agent to provideincreased stability; (ii) amino acid sequences designed to be cleaved byintestinal enzymes (e.g. pepsin, trypsin, chymotrypsin, elastase,carboxypeptidases A and B, etc.) provide for increased bioavailability;(iii) peptides longer than three amino acids for increased stability,increased anti-abuse e.g. less membrane permeability, and potentiallymore efficient intestinal digestion, e.g., major intestinal enzymestarget proteins and polypeptides, (iv) or mixtures thereof. In oneembodiment the carrier portion of the conjugate is designed forintestinal cleavage.

In another embodiment the cleavage specificity is directed to pepsinand/or chymotrypsin. Examples of carriers include XXXAA or XXAAA, whereX is selected from any amino acid, except Arg, Lys, His, Pro, and Metand A is selected from Tyr, Phe, Trp, or Leu. Examples of other carriersare selected from XXXPheLeu wherein X is Glu; XXXPheLeu wherein X isGly; XXPheLeuLeu wherein X is Glu; and XXPheLeuLeu wherein X is Gly.

In another embodiment the cleavage specificity is directed to trypsin.Examples of more carriers include XXXAA or XXAAA wherein X is any aminoacid except Pro and Cys and A is Arg or Lys. Examples of yet morecarriers are selected from XXXArgLeu wherein X is Glu; XXXArgLeu whereinX is Gly; XXArgLeuLeu wherein X is Gly; XXXArgLeuLeu wherein X is Gly.

Examples of chemical modifications to opioid agents that can be used incompositions described herein are disclosed in US Patent Application No:20050080012, which is herein incorporated by reference in its entirety.

In another embodiment, one or more adverse-effect-reducing active agentsin addition to the opioid antagonist agent or abuse deterrent componentcan be included in the dosage form. Adverse-effect-reducing activeagents include but are not limited to promethazine, dolasetron,granisetron, ondansetron, tropisetron, palonosetron, domperidone,droperidol, haloperidol, chlorpromazine, prochloperazine,metoclopramide, alizapride, cyclizine, diphenhydramine, dimenhydrinate,meclizine, hydroxyzine, cannabis, dronabinol, nabilone, midazolam,lorazepam, hyoscine, dexamethasone, trimethobenzamide, emetrol andpropofol.

Additives

The present compositions can further comprise suitable additives,including, but not limited to, diluents, binders, surfactants,lubricants, glidants, coating materials, plasticizers, coloring agents,flavoring agents, or pharmaceutically inert materials. Examples ofdiluents include, for example, cellulose; cellulose derivatives such asmicrocrystalline cellulose and the like; starch; starch derivatives suchas corn starch, cyclodextrin and the like; sugar; sugar alcohol such aslactose, D-mannitol and the like; inorganic diluents such as driedaluminum hydroxide gel, precipitated calcium carbonate, magnesiumaluminometasilicate, dibasic calcium phosphate and the like.

Examples of binders include, for example, hydroxypropylcellulose,methylcellulose, hydroxypropylmethylcellulose, povidone, dextrin,pullulane, hydroxypropyl starch, polyvinyl alcohol, scacia, agar,gelatin, tragacanth, macrogol and the like.

Examples of surfactants include, for example, sucrose esters of fattyacids, polyoxyl stearate, polyoxyethylene hydrogenated castor oil,polyoxyethylene polyoxypropylene glycol, sorbitan sesquioleate, sorbitantrioleate, sorbitan monostearate, sorbitan monopalmitate, sorbitanmonolaurate, polysorbate, glyceryl monostearate, sodium lauryl sulfate,lauromacrogol and the like.

Examples of lubricants include, for example, stearic acid, calciumstearate, magnesium stearate, talc and the like.

Examples of glidants include, for example, dried aluminum hydroxide gel,magnesium silicate and the like.

Examples of coating materials include, for example, hydroxypropylmethylcellulose 2910, aminoalkyl methacrylate copolymer E, polyvinylacetaldiethylaminoacetate, macrogol 6000, titanium oxide and the like.Examples of plasticizers include, for example, triethyl citrate,triacetin, macrogol 6000 and the like.

Administration

Described herein are methods for preventing an adverse effect such asnausea, vomiting, other gastric upsets, skin rashes, itching, allergicreactions such as swelling, difficulty breathing, closing of throat,abdominal pain, unusual bleeding or bruising, skin rashes, sedation, CNSdepression, or respiratory depression in a subject receiving, or in needof, opioid analgesic therapy. The prevention of an adverse effect can beaccomplished by the administration of an effective amount ofpromethazine or other antihistamine with the chosen analgesic agent oragents. In one embodiment, the invention provides methods for treatingpain, comprising administering to a subject in need thereof an effectiveamount of an opioid analgesic agent, a non-opioid analgesic agent, anagent that reduces side effects of the opioid analgesic agent andoptionally a stimulant agent. In one embodiment, the non-opioidanalgesic agent is acetaminophen. In another embodiment, the agent thatreduces an adverse effect is promethazine. In another embodiment, theinvention provides methods for treating pain, comprising administeringto a subject in need thereof an effective amount of an opioid analgesicagent, a non-opioid analgesic agent, a barbiturate agent, an agent thatreduces side effects of the opioid analgesic agent and optionally astimulant agent. In another embodiment, the invention provides methodsfor treating pain, comprising administering to a subject in need thereofan effective amount of an opioid analgesic agent, a barbiturate agent,an agent that reduces side effects of the opioid analgesic agent andoptionally a stimulant agent. In another embodiment, the inventionprovides methods for treating pain, comprising administering to asubject in need thereof an effective amount of a non-opioid analgesicagent, a barbiturate agent, an agent that reduces side effects of theopioid analgesic agent and optionally a stimulant agent. In anotherembodiment, the invention provides methods for treating pain, comprisingadministering to a subject in need thereof an effective amount of anopioid analgesic agent, an agent that reduces side effects of the opioidanalgesic agent and optionally a stimulant agent.

The administration can continue for only a relatively short time in thecase of an acute condition requiring opioid therapy or for long periodsin the case of conditions requiring chronic use of opioid analgesics.The dosing of analgesics can be dependent upon the condition beingtreated, the subject's individual perception of pain and the use of theopioid on a set time schedule as a prophylactic to prevent the onset ofpain or on an as needed basis in response to perceived pain. The choiceof selecting a dosage of a composition that contains suitable amount ofpromethazine can be dependent upon the extent and severity of theadverse effects including nausea, vomiting, other gastric upsets, skinrashes, allergic reactions such as swelling, difficulty breathing,closing of throat, abdominal pain, unusual bleeding or bruising, skinrashes, sedation, CNS depression, or respiratory depression in asubject, upon the sensitivity to side-effect-reducing compounds such aspromethazine in a subject, upon the likelihood of subject losingmedication by vomiting, and/or on an as needed basis in response toperceived adverse effects. The dosage can be assessed by a prescribingprofessional evaluating the subject, the condition treated, theanalgesic to be used, diet and the expected duration of therapy.

In one embodiment, compositions and methods described herein providesfor a method for treating a subject suffering from or susceptible topain, comprising administering to said subject an effective amount of acomposition comprising an effective amount of a first component which isa non-opioid analgesic, or a pharmaceutically acceptable salt thereof,an effective amount of a second component which is a non-opioidanalgesic, or a pharmaceutically acceptable salt thereof and aneffective amount of a third component which is an antihistamine.

In another embodiment, a method for treating a subject is providedcomprising administering an effective amount of a compositioncomprising: an effective amount of a first pharmaceutically active agentwhich is an opioid analgesic, or a pharmaceutically acceptable saltthereof; an effective amount of a second pharmaceutically active agentwhich is a non-opioid analgesic, or a pharmaceutically acceptable saltthereof; and an effective amount of a third pharmaceutically activeagent which is an antihistamine or an anti-emetic. In one embodiment theat least one adverse effect is nausea, vomiting, other gastric upsets,skin rashes, allergic reactions such as swelling, difficulty breathing,closing of throat, itching, abdominal pain, unusual bleeding orbruising, skin rashes, sedation, CNS depression, or respiratorydepression. In one embodiment the non-opioid analgesic is acetaminophenor analogue thereof. In one embodiment, the antihistamine ispromethazine. In one embodiment, the opioid analgesic is hydrocodone. Inanother embodiment the opioid analgesic is oxycodone. In anotherembodiment, the invention provides methods for preventing orameliorating an adverse effect associated with administration of ananalgesic, comprising administering to a subject in need thereof aneffective amount of an opioid analgesic agent, a non-opioid analgesicagent, an agent that reduces side effects of the opioid analgesic agentand optionally a stimulant agent. In one embodiment, the non-opioidanalgesic agent is acetaminophen. In another embodiment, the agent thatreduces an adverse effect is promethazine. In another embodiment, theinvention provides methods for preventing or ameliorating an adverseeffect associated with administration of an analgesic, comprisingadministering to a subject in need thereof an effective amount of anopioid analgesic agent, a non-opioid analgesic agent, a barbiturateagent, an agent that reduces side effects of the opioid analgesic agentand optionally a stimulant agent. In another embodiment, the inventionprovides methods for preventing or ameliorating an adverse effectassociated with administration of an analgesic, comprising administeringto a subject in need thereof an effective amount of an opioid analgesicagent, a barbiturate agent, an agent that reduces side effects of theopioid analgesic agent and optionally a stimulant agent. In anotherembodiment, the invention provides methods for preventing orameliorating an adverse effect associated with administration of ananalgesic, comprising administering to a subject in need thereof aneffective amount of a non-opioid analgesic agent, a barbiturate agent,an agent that reduces side effects of the opioid analgesic agent andoptionally a stimulant agent. In another embodiment, the inventionprovides methods for preventing or ameliorating an adverse effectassociated with administration of an analgesic, comprising administeringto a subject in need thereof an effective amount of an opioid analgesicagent, an agent that reduces side effects of the opioid analgesic agentand optionally a stimulant agent.

In another embodiment, compositions and methods described hereinprovides for a method for preventing an adverse effect such as nausea,vomiting, and a skin rash in a subject receiving or in need of opioidtherapy by the administration of an effective amount of acetaminophen oranalogue thereof and promethazine with the opioid analgesic agent. Inone embodiment, the opioid analgesic is hydrocodone. In anotherembodiment the opioid analgesic is oxycodone. In one embodiment,administration of a composition comprising a non-opioid analgesic and anantihistamine enhances the reduction or elimination of adverse effectsassociated with an opioid analgesic. For example, addition ofpromethazine and acetaminophen/ibuprofen reduces or eliminates anadverse effect associated with an opioid analgesic in a synergisticmanner.

It is believed that administration of a composition of the inventionwould result in treatment of the subject which includes elimination orreduction of an adverse effect associated with analgesics (e.g.,opioids) and enhance the beneficial uses of such analgesics. Such anadverse effect can otherwise render administration of certain analgesicsintolerable, due to for example vomiting, nausea, and skin rashes.Therefore, various embodiments of the methods of the invention aredirected to target populations of subjects that are susceptible to suchan adverse effect(s), thus allowing such subjects to benefit from thepain-alleviating effects of analgesic-based pain relief, administrationof which would otherwise be intolerable.

For example, by reducing the risk of vomiting, the risk of subjectlosing the analgesics (and losing the pain-relieving beneficial effectsof analgesics) by vomiting is minimized. Furthermore, administration canbe adjusted to provide the dose of side-effect-reducing compound tomatch the subject's analgesic ingestion without separate intervention bythe health care professionals. Adding one or more additional activeagents, such as promethazine, to the present compositions is believed toresult in a composition having reduced potential for abuse anddiversion.

Routes of Administration

In various embodiments, the active agents are formulated to beadministered through oral dosage forms (e.g., tablets, capsules, gels,lollipops), inhalations, nasal sprays, patches, absorbing gels, liquids,liquid tannates, suppositories, injections, I.V. drips, other deliverymethods, or a combination thereof to treat subjects. Administration maybe performed in a variety of ways, including, but not limited to orally,subcutaneously, intravenously, intranasally, intraotically,transdermally, topically (e.g., gels, salves, lotions, creams, etc.),intraperitoneally, intramuscularly, intrapulmonary (e.g., AERx®inhalable technology commercially available from Aradigm, or Inhance,pulmonary delivery system commercially available from InhaleTherapeutics), vaginally, parenterally, rectally, or intraocularly.

To prepare the present compositions, an effective amount of activeagents can be mixed with a suitable pharmaceutically acceptable carrier.Upon mixing of the compounds, the resulting composition can be a solid,a half-solid, a solution, suspension, or an emulsion. Such compositionscan be prepared according to methods known to those skilled in the art.The forms of the resulting compositions can depend upon a variety offactors, including the intended mode of administration and thesolubility of the compounds in the selected carrier or vehicle. Theeffective concentration of analgesics is sufficient for lessening oralleviating pain. In one embodiment of the invention, the components ofthe present compositions are at least one opioid analgesic agent (e.g.,hydrocodone/oxycodone), one non-opioid analgesic agent (e.g.,acetaminophen), and one antihistamine agent (e.g., promethazine). Inother embodiments, administration comprises administration of anantihistamine (e.g., promethazine) separately, prior to, or duringadministration of the analgesic formulations described herein (e.g.,which comprises hydrocodone and acetaminophen). In another embodimentthe components of the present compositions are at least one opioidanalgesic agent, a non-opioid analgesic agent, an agent that reducesside effects of the opioid analgesic agent and a stimulant agent. Inanother embodiment, the components of the present compositions are atleast one opioid analgesic agent, a non-opioid analgesic agent, abarbiturate agent, an agent that reduces side effects of the opioidanalgesic agent and optionally a stimulant agent. In another embodiment,the components of the present compositions are at least one opioidanalgesic agent, a barbiturate agent, an agent that reduces side effectsof the opioid analgesic agent and optionally a stimulant agent. Inanother embodiment, the components of the present compositions are atleast one non-opioid analgesic agent, a barbiturate agent, an agent thatreduces side effects of the opioid analgesic agent and optionally astimulant agent. In another embodiment, components of the presentcompositions are at least one opioid analgesic agent, an agent thatreduces side effects of the opioid analgesic agent and optionally astimulant agent.

The agents of the compositions and methods described herein can beadministered by the nasal inhalation route using conventional nebulizersor by oxygen aerosolization to provide convenient pain relief withreduced adverse effects. The agents can be suspended or dissolved in apharmacologically acceptable inhalation carrier. Examples of suchcarriers are distilled water, water/ethanol mixtures, and physiologicalsaline solution. Conventional additives including sodium chloride,glucose, citric acid and the like may be employed in these dosage formsto stabilize or to provide isotonic media. In one embodiment of theinvention, the compositions suitable for nasal inhalation by oxygenaerosolization administration comprise hydrocodone or oxycodone,acetaminophen, and promethazine. In other embodiments, an antihistamine(e.g., promethazine) can be administered separately, prior to, or duringadministration of the compositions described herein (e.g., thosecomprising hydrocodone and acetaminophen).

The agents described herein can also be administered as a self-propelleddosage unit in aerosol form suitable for inhalation therapy. Suitablemeans for employing the aerosol inhalation therapy technique aredescribed, for example, in U.S. Pat. No. 6,913,768 to Couch et al.,which is incorporated herein by reference in its entirety. The agent canbe suspended in an inert propellant such as a mixture ofdichlorodifluoromethane and dichlorotetrafluoroethane, together with aco-solvent such as ethanol, together with flavoring materials andstabilizers. In one embodiment of the invention, the agents useful for aself-propelled dosage unit in aerosol form administration arehydrocodone or oxycodone, acetaminophen, and promethazine. In a furtherembodiment the dosage unit may further comprise an agent such as abronchodilator (e.g., albuterol).

The agents of the compositions and methods described herein can also beadministered as nasal spray/drop compositions, which can convenientlyand safely be applied to subjects to effectively treat pain with reducedadverse effects. The compositions may further comprise a water solublepolymer such as polyvinylpyrrolidone, together with other medicationssuch as sumatriptan, together with bioadhesive material. In oneembodiment of the invention, the components of a composition for nasalspray or drop administration are hydrocodone or oxycodone agent,acetaminophen, and promethazine, or a pharmaceutically acceptable saltthereof.

The compositions described herein can also be administered topically tothe skin of a subject. The agents can be mixed with a pharmaceuticallyacceptable carrier or a base which is suitable for topical applicationto skin to form a dermatological composition. Suitable examples ofcarrier or base include, but not limited to, water, glycols, alcohols,lotions, creams, gels, emulsions, and sprays. A dermatologicalcomposition comprising an analgesic agent can be integrated into atopical dressing, medicated tape, dermal patch absorbing gel andcleansing tissues. In one embodiment of the invention, thedermatological composition comprises hydrocodone or oxycodone,acetaminophen, and promethazine.

The compositions described herein can also be in liquid or liquidtannate form. The liquid formulations can comprise, for example, anagent in water-in-solution and/or suspension form; and a vehiclecomprising polyethoxylated castor oil, alcohol and/or a polyoxyethylatedsorbitan mono-oleate with or without flavoring. Each dosage formcomprises an effective amount of an active agent and can optionallycomprise pharmaceutically inert agents, such as conventional excipients,vehicles, fillers, binders, disintegrants, pH adjusting substances,buffer, solvents, solubilizing agents, sweeteners, coloring agents andany other inactive agents that can be included in pharmaceutical dosageforms for oral administration. Examples of such vehicles and additivescan be found in Remington's Pharmaceutical Sciences, 17th edition(1985). Therefore, in one embodiment a liquid composition of theinvention comprises an opioid analgesic (e.g., hydrocodone oroxycodone), a non-opioid analgesic (e.g., acetaminophen) and anantihistamine (e.g., promethazine). In another embodiment a liquidcomposition of the invention comprises at least one opioid analgesicagent, a non-opioid analgesic agent, an agent that reduces side effectsof the opioid analgesic agent and a stimulant agent. In anotherembodiment, a liquid composition of the invention comprises at least oneopioid analgesic agent, a non-opioid analgesic agent, a barbiturateagent, an agent that reduces side effects of the opioid analgesic agentand optionally a stimulant agent. In another embodiment, a liquidcomposition of the invention comprises at least one opioid analgesicagent, a barbiturate agent, an agent that reduces side effects of theopioid analgesic agent and optionally a stimulant agent. In anotherembodiment, a liquid composition of the invention comprises at least onenon-opioid analgesic agent, a barbiturate agent, an agent that reducesside effects of the opioid analgesic agent and optionally a stimulantagent. In another embodiment, a liquid composition of the inventioncomprises at least one opioid analgesic agent, an agent that reducesside effects of the opioid analgesic agent and optionally a stimulantagent.

The compositions described herein can also be administered in asuppository form, comprising an outer layer containing the compositionin a suppository base. The suppository base may, for example, be anyconventional suppository base material such as glycogelatin,polyethylene glycol, fractionated palm kernel oil, or one or morenatural, synthetic or semi synthetic hard fats such as cocoa butter.Therefore, in one embodiment of the invention, the base material ismixed with an opioid analgesic (e.g., hydrocodone/oxycodone), anon-opioid analgesic (e.g., acetaminophen) and an antihistamine (e.g.,promethazine).

The compositions described herein can also be administered ininjection-ready stable liquids for injection or I.V. drip. For example,saline or other injection-ready liquid can be mixed with an opioidanalgesic (e.g., hydrocodone or oxycodone), a non-opioid analgesic(e.g., acetaminophen) and an antihistamine (e.g., promethazine). In oneembodiment a composition disclosed herein is administered by a subjectadministered injection. For example a subject can administer thecomposition via a hand-held injection device such as a pen typeinjector. In one example a subject can use a device or componentdisclosed in U.S. Pat. Nos. 6,146,361; 5,536,249; or 5,954,700 (whichare herein incorporated by reference in their entirety) to administer apharmaceutical composition disclosed herein.

Treatment or Prevention of Pain

The present compositions and methods are useful for treating orpreventing pain. Accordingly the present invention includes methods fortreating or preventing pain, comprising administering to a subject inneed thereof a composition of the invention. Pain treatable orpreventable includes, but is not limited to, pain associated withcancer, chronic or acute pain, headache pain, migraine headache, chronicheadache, surgical procedure, acute or chronic physical injury, bonefracture or crush injuries, spinal cord injury, inflammatory disease(e.g., pancreatitis), noninflammatory neuropathic or dysfunctional painconditions, or a combination thereof.

Various methods of drug administration known in the art or disclosedherein are utilized to deliver a composition of present invention to asubject in need thereof.

In some embodiments, methods of treatment or prevention comprisingadministering a composition of the invention are for treating pain orpreventing pain. In some embodiments, the pain treatable or preventablevia administration of a composition of the invention includes but is notlimited to headache pain, and/or headache related symptoms as furtherdescribed herein below.

Treatment or Prevention of Headache

The present compositions and methods are useful for treating orpreventing a headache. Preventable or treatable headaches include butare not limited to migraine headaches (with or without aura), clusterheadaches, chronic headaches, tension type headaches, HemicraniaContinua, new daily persistent, chronic tension type headaches or anycombination thereof. In one embodiment, a method for treating orpreventing a headache comprises administering to a subject in needthereof a composition of the invention. Each of such compositions iffully described herein.

Migraines and cluster headaches are both important, well-known, andextensively studied medical problem. In many cases, they completelyincapacitate a sufferer for the duration of the headache. Theirphysiological embodiments, causative and aggravating factors, andcurrent Treatments are discussed in detail in numerous scientificarticles, and in full-length medical textbooks such as Headache inClinical Practice (edited by S. Silberstein et al., Oxford Univ. Press,1998); The Headaches, by J. Olesen; and Headache Disorders: A ManagementGuide for Practitioners, by A. Rapoport and F. Sheftell (W. B. Saunders,Philadelphia, 1996), which are herein incorporated by reference in theirentirety. In addition, various definitions, categories, and diagnosticstandards are defined by standardized criteria that have been approvedand issued by the International Headache Society (IHS), which werepublished as a supplement to the journal Cephalalgia (Cephalalgia. 2004;24 Suppl 1:9-160) and is herein incorporated by reference in itsentirety.

In one embodiment a composition of the invention is administered to asubject to treat, eliminate or prevent at least one headache symptom. Aneffective amount is a dosage sufficient to reduce at least one symptomassociate with a headache. Headache symptoms include: (1) frequency,which can be evaluated over a span of time, such as number of suchheadaches per week, per month, or per year; (2) duration, whichevaluates (usually in hours) how long a headache lasts, from the time itbegins to develop into a migraine or cluster headache, until it has beenresolved; and (3) severity (also referred to as intensity), which isbased on subjective estimates of the severity or intensity of pain orother symptoms (such as nausea) being suffered by patients during suchheadaches. In one embodiment a composition is used in a method to reducethe frequency, duration or severity of a preventable or treatableheadache.

Treatment or Prevention of Photophobia

In one embodiment, the invention provides methods for treating orpreventing photophobia, comprising administering to a subject in needthereof a composition of the invention. In one embodiment thecomposition comprises an effective amount of each of an opioid analgesicand an antiemetic, as disclosed herein above. In one embodiment, theantiemetic is promethazine or a pharmaceutically acceptable salt thereofand the opioid analgesic is hydrocodone, oxycodone or a pharmaceuticallyacceptable salt thereof. In a further embodiment, the composition is inthe form of a bilayer tablet that comprises an immediate-release layerand a controlled-release layer. In another embodiment theimmediate-release layer comprises promethazine or a pharmaceuticallyacceptable salt thereof, and the controlled-release layer compriseshydrocodone, oxycodone or a pharmaceutically acceptable salt thereof. Ina further embodiment, the photophobia is associated with a migraineheadache.

In another embodiment, the invention provides methods for treating orpreventing photophobia, comprising administering to a subject in needthereof a composition comprising an effective amount of a triptan and aneffective amount of an antiemetic. In a further embodiment the triptanis a sumatriptan or a pharmaceutically acceptable salt thereof, and theantiemetic is promethazine or a pharmaceutically acceptable saltthereof. In one embodiment, the sumatriptan salt is sumatriptansuccinate.

In yet a further embodiment, the composition is in the form of a bilayertablet that comprises an immediate-release layer and acontrolled-release layer. In another embodiment of the invention thecontrolled-release layer comprises sumatriptan or a pharmaceuticallyacceptable salt thereof, and the immediate-release layer comprisespromethazine or a pharmaceutically acceptable salt thereof.

EXAMPLES Example 1

Example of an analgesic composition comprising Hydrocodone Bitartrate,Acetaminophen and Promethazine Hydrochloride

Analgesic Composition A Agents mg/Tablet Hydrocodone Bitartrate 7.5 mgAcetaminophen 325 mg Promethazine Hydrochloride 12.5 mg

Example 2

In one example, the composition of Example 1 is formulated in the formof a bi-layer tablet having an immediate-release layer comprising 12.5mg of promethazine hydrochloride and having a controlled-release layercomprising 7.5 mg of hydrocodone bitartrate and 325 mg of acetaminophen.

Example 3

The composition of Example 1 is orally administered with water to asubject having a tendency to exhibit adverse effects of opioidadministration, such as gastric upset, nausea, vomiting, skin rash,sedation, CNS depression, or respiratory depression. Such subjects, upontaking the composition set forth in Example 1 will receive an effectiveamount of promethazine in their blood stream. The promethazine willreduce the adverse effects that such a target population would otherwiseexhibit.

Example 4

Example of an analgesic composition comprising Oxycodone Hydrochloride,Acetaminophen and Promethazine Hydrochloride

Analgesic Composition B Agents mg/Tablet Oxycodone HCl 5 mg or 7.5 mgAcetaminophen 325 mg Promethazine Hydrochloride 12.5 mg

Example 5

In one example, the composition of Example 4 is in the form of abi-layer tablet having an immediate-release layer comprising 12.5 mg ofpromethazine hydrochloride, and having a controlled-release layercomprising 5 or 7.5 mg of oxycodone HCl and 325 mg of acetaminophen.

Example 6

The composition of Example 5 is orally administered with water to asubject having a tendency to exhibit adverse effects of opioidadministration, such as gastric upset, nausea, vomiting, skin rash,sedation, CNS depression, or respiratory depression. Such subjects, upontaking the composition set forth in Example 5 will receive an effectiveamount of promethazine which will reduce the adverse effects that such atarget population would otherwise exhibit.

Example 7

Example of an abuse safeguard drug formulation comprising HydrocodoneBitartrate, Acetaminophen and Promethazine Hydrochloride.

Analgesic Composition C Agents mg/Tablet Hydrocodone Bitartrate 7.5 mgAcetaminophen 325 mg Promethazine HCl 12.5 mg Naltrexone 0.75 mg

Example 8

In one example, the composition of Example 7 is in the form of abi-layered tablet having an immediate-release layer comprising 12.5 mgof promethazine hydrochloride, and having a controlled-release layercomprising 7.5 mg of hydrocodone bitartrate and 325 mg of acetaminophen.

Example 9

The composition of Example 7 is orally administered with water to asubject having a tendency to exhibit adverse effects of opioidadministration, such as gastric upset, nausea, vomiting, skin rash,sedation, CNS depression, or respiratory depression. Such subjects, upontaking the composition set forth in Example 7 will receive an effectiveamount of promethazine in their blood stream. The promethazine willreduce the adverse effects that such a target population would otherwiseexhibit.

Example 10

Example of an abuse safeguard drug formulation comprising Oxycodone HCl,Acetaminophen and Promethazine HCl.

Analgesic Composition D Agents mg/Tablet Oxycodone HCl 5 mg or 7.5 mgAcetaminophen 325 mg Promethazine HCl 12.5 mg Naltrexone 0.5 mg or 0.75mg 

Example 11

In one example, the composition of Example 10 is in the form of abi-layer tablet having an immediate-release layer comprising 12.5 mg ofpromethazine hydrochloride, and having a controlled-release layercomprising 5 or 7.5 mg of oxycodone HCl and 325 mg of acetaminophen.

Example 12

The composition of Example 10 is orally administered with water to asubject having a tendency to exhibit adverse effects of opioidadministration, such as gastric upset, nausea, vomiting, skin rash,sedation, CNS depression, or respiratory depression. Such subjects, upontaking the composition set forth in Example 10 will receive an effectiveamount of promethazine in their blood stream. The promethazine willreduce the adverse effects that such a target population would otherwiseexhibit.

Example 13

Example of a bi-layer tablet analgesic composition comprisingHydrocodone or a Pharmaceutically Acceptable Salt Thereof, Acetaminophenand Promethazine or a Pharmaceutically Acceptable Salt Thereof. In oneexample, a bi-layer tablet comprises: (1) a controlled-release layercomprising (a) from about 6.5 mg to about 8.5 mg of hydrocodone or apharmaceutically acceptable salt thereof, (b) from about 290 to about360 mg of acetaminophen or a pharmaceutically acceptable salt thereof,(c) from about 135 mg to about 170 mg of silicified microcrystallinecellulose, (d) from about 17 mg to about 23 mg of hydroxy methyl propylcellulose, (e) from about 1 mg to about 4 mg of magnesium stearate, and(f) from about 1 mg to about 4 mg of stearic acid; and (2) animmediate-release layer comprising (a) from about 11 mg to about 14 mgof promethazine or a pharmaceutically acceptable salt thereof, (b) fromabout 100 mg to about 140 mg of silicified microcrystalline cellulose,(c) from about 12 mg to about 18 mg of croscarmellose sodium and (d)from about 0.8 mg to about 1.5 mg of magnesium stearate. In anotherexample, a bi-layer tablet's controlled-release layer comprises about7.5 mg of hydrocodone or a pharmaceutically acceptable salt thereof,about 325 mg of acetaminophen or a pharmaceutically acceptable saltthereof, about 152 mg of silicified microcrystalline cellulose, about 20mg of hydroxy methyl propyl cellulose, about 2.7 mg of magnesiumstearate, and about 2.7 mg of stearic acid; and tablet's immediaterelease layer comprises about 12.5 mg of promethazine or apharmaceutically acceptable salt thereof, about 121.5 mg of silicifiedmicrocrystalline cellulose, about 15 mg of croscarmellose sodium andabout 1 mg of magnesium stearate.

Analgesic Composition F.1

Top Layer—Immediate Release Layer

Ingredient Quantity/Tablet (mg) Promethazine HCl 12.5 mg Prosolve SMCC(HD90) 121.5 mg Croscarmellose Sodium 15 mg Crospovidone NF 15 mg AvicelPH200 21.5 mg Magnesium Stearate 1 mg Total Top Layer Weight 186.5 mg

Bottom Layer—Controlled-Release Layer

Ingredient Quantity/Tablet (mg) Acetaminophen 89.5% 360.5 mg HydrocodoneBitartrate 7.5 mg Silicified Microcrystalline Cellulose 150 mg HydroxyMethyl Propyl Cellulose 10 mg Croscarmellose Sodium 23 mg MagnesiumStearate 15 mg Total Bottom Layer Weight 566 mg

Analgesic Composition F.2

Top Layer—Immediate Release Layer

Ingredient Quantity/Tablet (mg) Promethazine HCl 12.5 mg SilicifiedMicrocrystalline Cellulose 121.5 mg Croscarmellose Sodium 15 mgMagnesium Stearate 1 mg Total Top Layer Weight 150.0 mg

Bottom Layer—Controlled-Release Layer

Ingredient Quantity/Tablet (mg) Acetaminophen 89.05% 364.96 mgHydrocodone bitartrate 7.5 mg Silicified Microcrystalline Cellulose152.04 mg Hydroxy Methyl Propyl Cellulose 20 mg Stearic Acid 2.75 mgMagnesium Stearate 2.75 mg Total Bottom Layer Weight 566 mg

Example 14

The composition of Example 13 is orally administered with water to asubject having a tendency to exhibit adverse effects of opioidadministration, such as gastric upset, nausea, vomiting, skin rash,sedation, CNS depression, or respiratory depression. Such subjects, upontaking the composition set forth in Example 13 will receive an effectiveamount of promethazine in their blood stream. The promethazine willreduce the adverse effects that such a target population would otherwiseexhibit.

Example 15

Dissolution Data

Dissolution apparatus was a USP Rotating Paddle Apparatus 2 with anautomated sampling station (e.g., VK-8000 or equivalent). Dissolutionfluid was 900 mL of de-aerated 0.01 N HCl, maintained at 37.0+/−0.5° C.during dissolution procedure. The fluid was prepared by diluting 5 mL ofconcentrated HCl in 6000 mL of de-aerated water, and mixed. To measurepeaks, a dual wavelength detector (e.g., Hitachi L-2420) was used, oralternatively, two separate chromatographic systems can be used in orderto measure the peaks at two different wavelengths.

Standard Solution Preparation: Each ingredient was weighed (e.g., 21 mgof hydrocodone bitartrate) into a 50 mL volumetric flask, and diluted tovolume with dissolution media. The resulting solution was mixed to forma stock solution. Different ingredients were similarly prepared toprovide stock solutions (e.g., promethazine HCl, acetaminophen). 2 mLeach of stock standard solutions were diluted with dissolution fluid andmixed to produce a final standard solution. For example, theconcentration of hydrocodone bitartrate was about 0.0084 mg/mL,promethazine HCl was about 0.014 mg/mL, and acetaminophen was about 0.36mg/mL.

Dissolution test solutions were prepared in 900 mL of 0.01 N HCl usingthe USP Rotating Paddle Apparatus at 50 WM. An aliquot of thedissolution solution was filtered and a 50-pL aliquot waschromatographed on a 50-mm×4.6-mm (i.d.) Waters sunFire™ C₁₈, 3.5-μmparticle size column using a gradient HPLC method. Mobile phase Aconsisted of water/acetonitrile/TFA, 950/50/2 (v/v/v) and mobile phase Bconsisted of water/acetonitrile/TFA, 50/950/1.5 (v/v/v). The flow ratewas 2.0 mL/minute. For example, the amount of acetaminophen released wasdetermined at 300 nm by comparing the area obtained for the peak due toacetaminophen in the chromatogram of the dissolution test solution tothat obtained for the corresponding peak in a chromatogram of a standardsolution. The amount of hydrocodone bitartrate released was determinedat 230 nm by comparing the area obtained for the peak due to hydrocodonebitartrate in the chromatogram of the dissolution test solution to thatobtained for the corresponding peak in a chromatogram of a standardsolution. The amount of promethazine HCl released was determined at 230nm by comparing the area obtained for the peak due to promethazine HClin the chromatogram of the dissolution test solution to that obtainedfor the corresponding peak in a chromatogram of a standard solution.

Paddle speed was 50 rpm; pull volume was 10 mL (no replacement); Pullpoints: 5, 10, 15, 20, 25, 30, 45 and 60 minutes. The amount of eachcomponent dissolved in the dissolution medium was determined by HPLC.The method can use a high purity, bonded C18 stationary phase and abinary mobile phase consisting of an appropriate buffer and organicmodifier.

Dissolution Procedure. 900 mL of dissolution fluid preheated to 37° C.was placed into each vessel. Tablets of Analgesic Composition F.2 abovewere weighed and placed in vessels respectively. At prescribed timeintervals, 5 mL aliquot of the dissolution fluid was drawn using theautomated sampling station equipped with a 35 μm full flow filterconnected to a sampling probe. Filtrate was allowed to cool to roomtemperature, to produce a final sample solution. Fluid withdrawn was notreplaced. Samples were injected in HPLC for analysis after a baselinewas established. Peak area responses were measured for each component:acetaminophen peak eluted at about 1.5 minutes; hydrocodone bitartrateeluted at about 3.3 minutes and promethazine HCl eluted at about 4.8minutes. The resolution between each peak was calculated, as well as thetailing factor. The mean and % RSD values for the acetaminophen peakareas at 300 nm were measured; promethazine HCl and hydrocodonebitartrate at 230 nm. The five replicate injections were not more than2.0% RSD. 50 μL aliquots of standard and sample solutions were subjectedto liquid chromatography. A typical chromatogram of a standard solutionis illustrated in FIG. 1.

The amount of a pharmaceutically active agent in a tablet is determinedby comparing the area obtained for the peak due to the agent in achromatogram of the dissolution test solution to that obtained for thecorresponding peak in a chromatogram of a standard solution. For examplethe standard peaks are provided in FIG. 3, while the test solutions areprovide in FIG. 4.

Example 16

The compositions of Table 1 or Table 2 can be formulated in formulatedin a variety of dosage forms (e.g., tablets, capsules, geld, lollipops),parenteral, intraspinal infusion, inhalations, nasal sprays, transdermalpatches, iontophoresis transport, absorbing gels, liquids, liquidtannates, suppositories, injections, I.V. drips, other delivery methods,or a combination thereof to treat subjects. In some embodiments eachagent disclosed in Table 1 or Table 2 can be present in a composition asits pharmaceutically acceptable salt. In one embodiment the hydrocodoneof the compositions of Table 1 is in the form of hydrocodone bitartrate;in another embodiment the oxycodone of the compositions of Table 1 is inthe form of oxycodone hydrochloride; in another embodiment the ibuprofenof the compositions of Table 1 is in the form of ibuprofen sodium; inanother embodiment the naproxen of the compositions of Table 1 is in theform of naproxen sodium; in another embodiment the promethazine of thecompositions of Table 1 or Table 2 is in the form of promethazinehydrochloride; and in another embodiment the naltrexone of thecompositions of Table 1 is in the form of naltrexone hydrochloride. Insome embodiments a dosage form comprising an effective amount ofpromethazine or a pharmaceutically acceptable salt thereof will beorally administered to a subject having a tendency to exhibit one ormore adverse effect of opioid administration, such as gastric upset,nausea, vomiting, skin rash, sedation, CNS depression, or respiratorydepression in response to opioid administration. In one embodiment oneor more of compositions of Table 1 or Table 2 are in the form of abi-layer tablet comprising an immediate release layer and a controlledrelease layer. In one embodiment the controlled-release layer compriseshydrocodone, oxycodone, propoxyphene, ibuprofen, acetaminophen, naproxenor a pharmaceutically acceptable salt thereof and the immediate-releaselayer comprises promethazine or a pharmaceutically acceptable saltthereof.

TABLE 1 Multi-drug Compositions Opioid Abuse Composition Non-opioidAntiemetic Barbiturate Stimulant antagonist deterrent No. Opioid agentagent agent agent agent agent agent 1 Hydrocodone Acetaminophen — — — —— 2 Hydrocodone — Promethazine — — — — 3 Hydrocodone — — Butalbital — —— 4 Hydrocodone — — — Modafinil — — 5 Hydrocodone — — — Caffeine — — 6Hydrocodone — — — — Naltrexone — 7 Hydrocodone — — — — — Niacin 8Hydrocodone Acetaminophen Promethazine — — — — 9 HydrocodoneAcetaminophen — Butalbital — — — 10 Hydrocodone Acetaminophen — —Modafinil — — 11 Hydrocodone Acetaminophen — — Caffeine — — 12Hydrocodone Acetaminophen — — — Naltrexone — 13 HydrocodoneAcetaminophen — — — — Niacin 14 Hydrocodone — Promethazine Butalbital —— — 15 Hydrocodone — Promethazine — Modafinil — — 16 Hydrocodone —Promethazine — Caffeine — — 17 Hydrocodone — Promethazine — — Naltrexone— 18 Hydrocodone — Promethazine — — — Niacin 19 Hydrocodone — —Butalbital Modafinil — — 20 Hydrocodone — — Butalbital Caffeine — — 21Hydrocodone — — Butalbital — Naltrexone — 22 Hydrocodone — — Butalbital— — Niacin 23 Hydrocodone — — — Modafinil Naltrexone — 24 Hydrocodone —— — Caffeine Naltrexone — 25 Hydrocodone — — — Modafinil — Niacin 26Hydrocodone — — — Caffeine — Niacin 27 Hydrocodone — — — — NaltrexoneNiacin 28 Hydrocodone Acetaminophen Promethazine Butalbital — — — 29Hydrocodone Acetaminophen Promethazine — Modafinil — — 30 HydrocodoneAcetaminophen Promethazine — Caffeine — — 31 Hydrocodone AcetaminophenPromethazine — — Naltrexone — 32 Hydrocodone Acetaminophen Promethazine— — — Niacin 33 Hydrocodone Acetaminophen — Butalbital Modafinil — — 34Hydrocodone Acetaminophen — Butalbital Caffeine — — 35 HydrocodoneAcetaminophen — Butalbital — Naltrexone — 36 Hydrocodone Acetaminophen —Butalbital — — Niacin 37 Hydrocodone Acetaminophen — — ModafinilNaltrexone — 38 Hydrocodone Acetaminophen — — Modafinil — Niacin 39Hydrocodone Acetaminophen — — Caffeine Naltrexone — 40 HydrocodoneAcetaminophen — — Caffeine — Niacin 41 Hydrocodone Acetaminophen — — —Naltrexone Niacin 42 Hydrocodone — Promethazine Butalbital Modafinil — —43 Hydrocodone — Promethazine Butalbital Caffeine — — 44 Hydrocodone —Promethazine Butalbital — Naltrexone — 45 Hydrocodone — PromethazineButalbital — — Niacin 46 Hydrocodone — Promethazine — ModafinilNaltrexone — 47 Hydrocodone — Promethazine — Caffeine Naltrexone — 48Hydrocodone — Promethazine — Modafinil — Niacin 49 Hydrocodone —Promethazine — Caffeine — Niacin 50 Hydrocodone — Promethazine — —Naltrexone Niacin 51 Hydrocodone — — Butalbital Modafinil Naltrexone —52 Hydrocodone — — Butalbital Caffeine Naltrexone — 53 Hydrocodone — —Butalbital Modafinil — Niacin 54 Hydrocodone — — Butalbital Caffeine —Niacin 55 Hydrocodone — — Butalbital — Naltrexone Niacin 56 Hydrocodone— — — Modafinil Naltrexone Niacin 57 Hydrocodone — — — CaffeineNaltrexone Niacin 58 Hydrocodone Acetaminophen Promethazine ButalbitalModafinil — — 59 Hydrocodone Acetaminophen Promethazine ButalbitalCaffeine — — 60 Hydrocodone Acetaminophen Promethazine Butalbital —Naltrexone — 61 Hydrocodone Acetaminophen Promethazine Butalbital — —Niacin 62 Hydrocodone Acetaminophen Promethazine — Modafinil Naltrexone— 63 Hydrocodone Acetaminophen Promethazine — Caffeine Naltrexone — 64Hydrocodone Acetaminophen Promethazine — Modafinil — Niacin 65Hydrocodone Acetaminophen Promethazine — Caffeine — Niacin 66Hydrocodone Acetaminophen Promethazine — — Naltrexone Niacin 67Hydrocodone Acetaminophen — Butalbital Modafinil Naltrexone — 68Hydrocodone Acetaminophen — Butalbital Caffeine Naltrexone — 69Hydrocodone Acetaminophen — Butalbital Modafinil — Niacin 70 HydrocodoneAcetaminophen — Butalbital Caffeine — Niacin 71 HydrocodoneAcetaminophen — Butalbital — Naltrexone Niacin 72 HydrocodoneAcetaminophen — — Modafinil Naltrexone Niacin 73 HydrocodoneAcetaminophen — — Caffeine Naltrexone Niacin 74 Hydrocodone —Promethazine Butalbital Modafinil Naltrexone — 75 Hydrocodone —Promethazine Butalbital Caffeine Naltrexone — 76 Hydrocodone —Promethazine Butalbital Modafinil — Niacin 77 Hydrocodone — PromethazineButalbital Caffeine — Niacin 78 Hydrocodone — Promethazine Butalbital —Naltrexone Niacin 79 Hydrocodone — — Butalbital Caffeine NaltrexoneNiacin 80 Hydrocodone Acetaminophen Promethazine Butalbital ModafinilNaltrexone — 81 Hydrocodone Acetaminophen Promethazine ButalbitalCaffeine Naltrexone — 82 Hydrocodone Acetaminophen PromethazineButalbital Modafinil — Niacin 83 Hydrocodone Acetaminophen PromethazineButalbital Caffeine — Niacin 84 Hydrocodone — Promethazine ButalbitalModafinil Naltrexone Niacin 85 Hydrocodone — Promethazine ButalbitalCaffeine Naltrexone Niacin 86 Hydrocodone Acetaminophen — ButalbitalModafinil Naltrexone Niacin 87 Hydrocodone Acetaminophen — ButalbitalCaffeine Naltrexone Niacin 88 Hydrocodone Acetaminophen Promethazine —Modafinil Naltrexone Niacin 89 Hydrocodone Acetaminophen Promethazine —Caffeine Naltrexone Niacin 90 Hydrocodone Acetaminophen PromethazineButalbital — Naltrexone Niacin 91 Hydrocodone Acetaminophen PromethazineButalbital Modafinil Naltrexone Niacin 92 Hydrocodone AcetaminophenPromethazine Butalbital Caffeine Naltrexone Niacin 93 HydrocodoneNaproxen — — — — — 94 Hydrocodone — Promethazine — — — — 95 Hydrocodone— — Butalbital — — — 96 Hydrocodone — — — Modafinil — — 97 Hydrocodone —— — Caffeine — — 98 Hydrocodone — — — — Naltrexone — 99 Hydrocodone — —— — — Niacin 100 Hydrocodone Naproxen Promethazine — — — — 101Hydrocodone Naproxen — Butalbital — — — 102 Hydrocodone Naproxen — —Modafinil — — 103 Hydrocodone Naproxen — — Caffeine — — 104 HydrocodoneNaproxen — — — Naltrexone — 105 Hydrocodone Naproxen — — — — Niacin 106Hydrocodone — Promethazine Butalbital — — — 107 Hydrocodone —Promethazine — Modafinil — — 108 Hydrocodone — Promethazine — Caffeine —— 109 Hydrocodone — Promethazine — — Naltrexone — 110 Hydrocodone —Promethazine — — — Niacin 111 Hydrocodone — — Butalbital Modafinil — —112 Hydrocodone — — Butalbital Caffeine — — 113 Hydrocodone — —Butalbital — Naltrexone — 114 Hydrocodone — — Butalbital — — Niacin 115Hydrocodone — — — Modafinil Naltrexone — 116 Hydrocodone — — — CaffeineNaltrexone — 117 Hydrocodone — — — Modafinil — Niacin 118 Hydrocodone —— — Caffeine — Niacin 119 Hydrocodone — — — — Naltrexone Niacin 120Hydrocodone Naproxen Promethazine Butalbital — — — 121 HydrocodoneNaproxen Promethazine — Modafinil — — 122 Hydrocodone NaproxenPromethazine — Caffeine — — 123 Hydrocodone Naproxen Promethazine — —Naltrexone — 124 Hydrocodone Naproxen Promethazine — — — Niacin 125Hydrocodone Naproxen — Butalbital Modafinil — — 126 Hydrocodone Naproxen— Butalbital Caffeine — — 127 Hydrocodone Naproxen — Butalbital —Naltrexone — 128 Hydrocodone Naproxen — Butalbital — — Niacin 129Hydrocodone Naproxen — — Modafinil Naltrexone — 130 Hydrocodone Naproxen— — Modafinil — Niacin 131 Hydrocodone Naproxen — — Caffeine Naltrexone— 132 Hydrocodone Naproxen — — Caffeine — Niacin 133 HydrocodoneNaproxen — — — Naltrexone Niacin 134 Hydrocodone — PromethazineButalbital Modafinil — — 135 Hydrocodone — Promethazine ButalbitalCaffeine — — 136 Hydrocodone — Promethazine Butalbital — Naltrexone —137 Hydrocodone — Promethazine Butalbital — — Niacin 138 Hydrocodone —Promethazine — Modafinil Naltrexone — 139 Hydrocodone — Promethazine —Caffeine Naltrexone — 140 Hydrocodone — Promethazine — Modafinil —Niacin 141 Hydrocodone — Promethazine — Caffeine — Niacin 142Hydrocodone — Promethazine — — Naltrexone Niacin 143 Hydrocodone — —Butalbital Modafinil Naltrexone — 144 Hydrocodone — — ButalbitalCaffeine Naltrexone — 145 Hydrocodone — — Butalbital Modafinil — Niacin146 Hydrocodone — — Butalbital Caffeine — Niacin 147 Hydrocodone — —Butalbital — Naltrexone Niacin 148 Hydrocodone — — — ModafinilNaltrexone Niacin 149 Hydrocodone — — — Caffeine Naltrexone Niacin 150Hydrocodone Naproxen Promethazine Butalbital Modafinil — — 151Hydrocodone Naproxen Promethazine Butalbital Caffeine — — 152Hydrocodone Naproxen Promethazine Butalbital — Naltrexone — 153Hydrocodone Naproxen Promethazine Butalbital — — Niacin 154 HydrocodoneNaproxen Promethazine — Modafinil Naltrexone — 155 Hydrocodone NaproxenPromethazine — Caffeine Naltrexone — 156 Hydrocodone NaproxenPromethazine — Modafinil — Niacin 157 Hydrocodone Naproxen Promethazine— Caffeine — Niacin 158 Hydrocodone Naproxen Promethazine — — NaltrexoneNiacin 159 Hydrocodone Naproxen — Butalbital Modafinil Naltrexone — 160Hydrocodone Naproxen — Butalbital Caffeine Naltrexone — 161 HydrocodoneNaproxen — Butalbital Modafinil — Niacin 162 Hydrocodone Naproxen —Butalbital Caffeine — Niacin 163 Hydrocodone Naproxen — Butalbital —Naltrexone Niacin 164 Hydrocodone Naproxen — — Modafinil NaltrexoneNiacin 165 Hydrocodone Naproxen — — Caffeine Naltrexone Niacin 166Hydrocodone — Promethazine Butalbital Modafinil Naltrexone — 167Hydrocodone — Promethazine Butalbital Caffeine Naltrexone — 168Hydrocodone — Promethazine Butalbital Modafinil — Niacin 169 Hydrocodone— Promethazine Butalbital Caffeine — Niacin 170 Hydrocodone —Promethazine Butalbital — Naltrexone Niacin 171 Hydrocodone — —Butalbital Caffeine Naltrexone Niacin 172 Hydrocodone NaproxenPromethazine Butalbital Modafinil Naltrexone — 173 Hydrocodone NaproxenPromethazine Butalbital Caffeine Naltrexone — 174 Hydrocodone NaproxenPromethazine Butalbital Modafinil — Niacin 175 Hydrocodone NaproxenPromethazine Butalbital Caffeine — Niacin 176 Hydrocodone — PromethazineButalbital Modafinil Naltrexone Niacin 177 Hydrocodone — PromethazineButalbital Caffeine Naltrexone Niacin 178 Hydrocodone Naproxen —Butalbital Modafinil Naltrexone Niacin 179 Hydrocodone Naproxen —Butalbital Caffeine Naltrexone Niacin 180 Hydrocodone NaproxenPromethazine — Modafinil Naltrexone Niacin 181 Hydrocodone NaproxenPromethazine — Caffeine Naltrexone Niacin 182 Hydrocodone NaproxenPromethazine Butalbital — Naltrexone Niacin 183 Hydrocodone NaproxenPromethazine Butalbital Modafinil Naltrexone Niacin 184 HydrocodoneNaproxen Promethazine Butalbital Caffeine Naltrexone Niacin 185Hydrocodone Ibuprofen — — — — — 186 Hydrocodone — Promethazine — — — —187 Hydrocodone — — Butalbital — — — 188 Hydrocodone — — — Modafinil — —189 Hydrocodone — — — Caffeine — — 190 Hydrocodone — — — — Naltrexone —191 Hydrocodone — — — — — Niacin 192 Hydrocodone Ibuprofen Promethazine— — — — 193 Hydrocodone Ibuprofen — Butalbital — — — 194 HydrocodoneIbuprofen — — Modafinil — — 195 Hydrocodone Ibuprofen — — Caffeine — —196 Hydrocodone Ibuprofen — — — Naltrexone — 197 Hydrocodone Ibuprofen —— — — Niacin 198 Hydrocodone — Promethazine Butalbital — — — 199Hydrocodone — Promethazine — Modafinil — — 200 Hydrocodone —Promethazine — Caffeine — — 201 Hydrocodone — Promethazine — —Naltrexone — 202 Hydrocodone — Promethazine — — — Niacin 203 Hydrocodone— — Butalbital Modafinil — — 204 Hydrocodone — — Butalbital Caffeine — —205 Hydrocodone — — Butalbital — Naltrexone — 206 Hydrocodone — —Butalbital — — Niacin 207 Hydrocodone — — — Modafinil Naltrexone — 208Hydrocodone — — — Caffeine Naltrexone — 209 Hydrocodone — — — Modafinil— Niacin 210 Hydrocodone — — — Caffeine — Niacin 211 Hydrocodone — — — —Naltrexone Niacin 212 Hydrocodone Ibuprofen Promethazine Butalbital — —— 213 Hydrocodone Ibuprofen Promethazine — Modafinil — — 214 HydrocodoneIbuprofen Promethazine — Caffeine — — 215 Hydrocodone IbuprofenPromethazine — — Naltrexone — 216 Hydrocodone Ibuprofen Promethazine — —— Niacin 217 Hydrocodone Ibuprofen — Butalbital Modafinil — — 218Hydrocodone Ibuprofen — Butalbital Caffeine — — 219 HydrocodoneIbuprofen — Butalbital — Naltrexone — 220 Hydrocodone Ibuprofen —Butalbital — — Niacin 221 Hydrocodone Ibuprofen — — Modafinil Naltrexone— 222 Hydrocodone Ibuprofen — — Modafinil — Niacin 223 HydrocodoneIbuprofen — — Caffeine Naltrexone — 224 Hydrocodone Ibuprofen — —Caffeine — Niacin 225 Hydrocodone Ibuprofen — — — Naltrexone Niacin 226Hydrocodone — Promethazine Butalbital Modafinil — — 227 Hydrocodone —Promethazine Butalbital Caffeine — — 228 Hydrocodone — PromethazineButalbital — Naltrexone — 229 Hydrocodone — Promethazine Butalbital — —Niacin 230 Hydrocodone — Promethazine — Modafinil Naltrexone — 231Hydrocodone — Promethazine — Caffeine Naltrexone — 232 Hydrocodone —Promethazine — Modafinil — Niacin 233 Hydrocodone — Promethazine —Caffeine — Niacin 234 Hydrocodone — Promethazine — — Naltrexone Niacin235 Hydrocodone — — Butalbital Modafinil Naltrexone — 236 Hydrocodone —— Butalbital Caffeine Naltrexone — 237 Hydrocodone — — ButalbitalModafinil — Niacin 238 Hydrocodone — — Butalbital Caffeine — Niacin 239Hydrocodone — — Butalbital — Naltrexone Niacin 240 Hydrocodone — — —Modafinil Naltrexone Niacin 241 Hydrocodone — — — Caffeine NaltrexoneNiacin 242 Hydrocodone Ibuprofen Promethazine Butalbital Modafinil — —243 Hydrocodone Ibuprofen Promethazine Butalbital Caffeine — — 244Hydrocodone Ibuprofen Promethazine Butalbital — Naltrexone — 245Hydrocodone Ibuprofen Promethazine Butalbital — — Niacin 246 HydrocodoneIbuprofen Promethazine — Modafinil Naltrexone — 247 HydrocodoneIbuprofen Promethazine — Caffeine Naltrexone — 248 Hydrocodone IbuprofenPromethazine — Modafinil — Niacin 249 Hydrocodone Ibuprofen Promethazine— Caffeine — Niacin 250 Hydrocodone Ibuprofen Promethazine — —Naltrexone Niacin 251 Hydrocodone Ibuprofen — Butalbital ModafinilNaltrexone — 252 Hydrocodone Ibuprofen — Butalbital Caffeine Naltrexone— 253 Hydrocodone Ibuprofen — Butalbital Modafinil — Niacin 254Hydrocodone Ibuprofen — Butalbital Caffeine — Niacin 255 HydrocodoneIbuprofen — Butalbital — Naltrexone Niacin 256 Hydrocodone Ibuprofen — —Modafinil Naltrexone Niacin 257 Hydrocodone Ibuprofen — — CaffeineNaltrexone Niacin 258 Hydrocodone — Promethazine Butalbital ModafinilNaltrexone — 259 Hydrocodone — Promethazine Butalbital CaffeineNaltrexone — 260 Hydrocodone — Promethazine Butalbital Modafinil —Niacin 261 Hydrocodone — Promethazine Butalbital Caffeine — Niacin 262Hydrocodone — Promethazine Butalbital — Naltrexone Niacin 263Hydrocodone — — Butalbital Caffeine Naltrexone Niacin 264 HydrocodoneIbuprofen Promethazine Butalbital Modafinil Naltrexone — 265 HydrocodoneIbuprofen Promethazine Butalbital Caffeine Naltrexone — 266 HydrocodoneIbuprofen Promethazine Butalbital Modafinil — Niacin 267 HydrocodoneIbuprofen Promethazine Butalbital Caffeine — Niacin 268 Hydrocodone —Promethazine Butalbital Modafinil Naltrexone Niacin 269 Hydrocodone —Promethazine Butalbital Caffeine Naltrexone Niacin 270 HydrocodoneIbuprofen — Butalbital Modafinil Naltrexone Niacin 271 HydrocodoneIbuprofen — Butalbital Caffeine Naltrexone Niacin 272 HydrocodoneIbuprofen Promethazine — Modafinil Naltrexone Niacin 273 HydrocodoneIbuprofen Promethazine — Caffeine Naltrexone Niacin 274 HydrocodoneIbuprofen Promethazine Butalbital — Naltrexone Niacin 275 HydrocodoneIbuprofen Promethazine Butalbital Modafinil Naltrexone Niacin 276Hydrocodone Ibuprofen Promethazine Butalbital Caffeine Naltrexone Niacin277 Oxycodone Acetaminophen — — — — — 278 Oxycodone — Promethazine — — —— 279 Oxycodone — — Butalbital — — — 280 Oxycodone — — — Modafinil — —281 Oxycodone — — — Caffeine — — 282 Oxycodone — — — — Naltrexone — 283Oxycodone — — — — — Niacin 284 Oxycodone Acetaminophen Promethazine — —— — 285 Oxycodone Acetaminophen — Butalbital — — — 286 OxycodoneAcetaminophen — — Modafinil — — 287 Oxycodone Acetaminophen — — Caffeine— — 288 Oxycodone Acetaminophen — — — Naltrexone — 289 OxycodoneAcetaminophen — — — — Niacin 290 Oxycodone — Promethazine Butalbital — —— 291 Oxycodone — Promethazine — Modafinil — — 292 Oxycodone —Promethazine — Caffeine — — 293 Oxycodone — Promethazine — — Naltrexone— 294 Oxycodone — Promethazine — — — Niacin 295 Oxycodone — — ButalbitalModafinil — — 296 Oxycodone — — Butalbital Caffeine — — 297 Oxycodone —— Butalbital — Naltrexone — 298 Oxycodone — — Butalbital — — Niacin 299Oxycodone — — — Modafinil Naltrexone — 300 Oxycodone — — — CaffeineNaltrexone — 301 Oxycodone — — — Modafinil — Niacin 302 Oxycodone — — —Caffeine — Niacin 303 Oxycodone — — — — Naltrexone Niacin 304 OxycodoneAcetaminophen Promethazine Butalbital — — — 305 Oxycodone AcetaminophenPromethazine — Modafinil — — 306 Oxycodone Acetaminophen Promethazine —Caffeine — — 307 Oxycodone Acetaminophen Promethazine — — Naltrexone —308 Oxycodone Acetaminophen Promethazine — — — Niacin 309 OxycodoneAcetaminophen — Butalbital Modafinil — — 310 Oxycodone Acetaminophen —Butalbital Caffeine — — 311 Oxycodone Acetaminophen — Butalbital —Naltrexone — 312 Oxycodone Acetaminophen — Butalbital — — Niacin 313Oxycodone Acetaminophen — — Modafinil Naltrexone — 314 OxycodoneAcetaminophen — — Modafinil — Niacin 315 Oxycodone Acetaminophen — —Caffeine Naltrexone — 316 Oxycodone Acetaminophen — — Caffeine — Niacin317 Oxycodone Acetaminophen — — — Naltrexone Niacin 318 Oxycodone —Promethazine Butalbital Modafinil — — 319 Oxycodone — PromethazineButalbital Caffeine — — 320 Oxycodone — Promethazine Butalbital —Naltrexone — 321 Oxycodone — Promethazine Butalbital — — Niacin 322Oxycodone — Promethazine — Modafinil Naltrexone — 323 Oxycodone —Promethazine — Caffeine Naltrexone — 324 Oxycodone — Promethazine —Modafinil — Niacin 325 Oxycodone — Promethazine — Caffeine — Niacin 326Oxycodone — Promethazine — — Naltrexone Niacin 327 Oxycodone — —Butalbital Modafinil Naltrexone — 328 Oxycodone — — Butalbital CaffeineNaltrexone — 329 Oxycodone — — Butalbital Modafinil — Niacin 330Oxycodone — — Butalbital Caffeine — Niacin 331 Oxycodone — — Butalbital— Naltrexone Niacin 332 Oxycodone — — — Modafinil Naltrexone Niacin 333Oxycodone — — — Caffeine Naltrexone Niacin 334 Oxycodone AcetaminophenPromethazine Butalbital Modafinil — — 335 Oxycodone AcetaminophenPromethazine Butalbital Caffeine — — 336 Oxycodone AcetaminophenPromethazine Butalbital — Naltrexone — 337 Oxycodone AcetaminophenPromethazine Butalbital — — Niacin 338 Oxycodone AcetaminophenPromethazine — Modafinil Naltrexone — 339 Oxycodone AcetaminophenPromethazine — Caffeine Naltrexone — 340 Oxycodone AcetaminophenPromethazine — Modafinil — Niacin 341 Oxycodone AcetaminophenPromethazine — Caffeine — Niacin 342 Oxycodone AcetaminophenPromethazine — — Naltrexone Niacin 343 Oxycodone Acetaminophen —Butalbital Modafinil Naltrexone — 344 Oxycodone Acetaminophen —Butalbital Caffeine Naltrexone — 345 Oxycodone Acetaminophen —Butalbital Modafinil — Niacin 346 Oxycodone Acetaminophen — ButalbitalCaffeine — Niacin 347 Oxycodone Acetaminophen — Butalbital — NaltrexoneNiacin 348 Oxycodone Acetaminophen — — Modafinil Naltrexone Niacin 349Oxycodone Acetaminophen — — Caffeine Naltrexone Niacin 350 Oxycodone —Promethazine Butalbital Modafinil Naltrexone — 351 Oxycodone —Promethazine Butalbital Caffeine Naltrexone — 352 Oxycodone —Promethazine Butalbital Modafinil — Niacin 353 Oxycodone — PromethazineButalbital Caffeine — Niacin 354 Oxycodone — Promethazine Butalbital —Naltrexone Niacin 355 Oxycodone — — Butalbital Caffeine NaltrexoneNiacin 356 Oxycodone Acetaminophen Promethazine Butalbital ModafinilNaltrexone — 357 Oxycodone Acetaminophen Promethazine ButalbitalCaffeine Naltrexone — 358 Oxycodone Acetaminophen PromethazineButalbital Modafinil — Niacin 359 Oxycodone Acetaminophen PromethazineButalbital Caffeine — Niacin 360 Oxycodone — Promethazine ButalbitalModafinil Naltrexone Niacin 361 Oxycodone — Promethazine ButalbitalCaffeine Naltrexone Niacin 362 Oxycodone Acetaminophen — ButalbitalModafinil Naltrexone Niacin 363 Oxycodone Acetaminophen — ButalbitalCaffeine Naltrexone Niacin 364 Oxycodone Acetaminophen Promethazine —Modafinil Naltrexone Niacin 365 Oxycodone Acetaminophen Promethazine —Caffeine Naltrexone Niacin 366 Oxycodone Acetaminophen PromethazineButalbital — Naltrexone Niacin 367 Oxycodone Acetaminophen PromethazineButalbital Modafinil Naltrexone Niacin 368 Oxycodone AcetaminophenPromethazine Butalbital Caffeine Naltrexone Niacin 369 OxycodoneNaproxen — — — — — 370 Oxycodone — Promethazine — — — — 371 Oxycodone —— Butalbital — — — 372 Oxycodone — — — Modafinil — — 373 Oxycodone — — —Caffeine — — 374 Oxycodone — — — — Naltrexone — 375 Oxycodone — — — — —Niacin 376 Oxycodone Naproxen Promethazine — — — — 377 OxycodoneNaproxen — Butalbital — — — 378 Oxycodone Naproxen — — Modafinil — — 379Oxycodone Naproxen — — Caffeine — — 380 Oxycodone Naproxen — — —Naltrexone — 381 Oxycodone Naproxen — — — — Niacin 382 Oxycodone —Promethazine Butalbital — — — 383 Oxycodone — Promethazine — Modafinil —— 384 Oxycodone — Promethazine — Caffeine — — 385 Oxycodone —Promethazine — — Naltrexone — 386 Oxycodone — Promethazine — — — Niacin387 Oxycodone — — Butalbital Modafinil — — 388 Oxycodone — — ButalbitalCaffeine — — 389 Oxycodone — — Butalbital — Naltrexone — 390 Oxycodone —— Butalbital — — Niacin 391 Oxycodone — — — Modafinil Naltrexone — 392Oxycodone — — — Caffeine Naltrexone — 393 Oxycodone — — — Modafinil —Niacin 394 Oxycodone — — — Caffeine — Niacin 395 Oxycodone — — — —Naltrexone Niacin 396 Oxycodone Naproxen Promethazine Butalbital — — —397 Oxycodone Naproxen Promethazine — Modafinil — — 398 OxycodoneNaproxen Promethazine — Caffeine — — 399 Oxycodone Naproxen Promethazine— — Naltrexone — 400 Oxycodone Naproxen Promethazine — — — Niacin 401Oxycodone Naproxen — Butalbital Modafinil — — 402 Oxycodone Naproxen —Butalbital Caffeine — — 403 Oxycodone Naproxen — Butalbital — Naltrexone— 404 Oxycodone Naproxen — Butalbital — — Niacin 405 Oxycodone Naproxen— — Modafinil Naltrexone — 406 Oxycodone Naproxen — — Modafinil — Niacin407 Oxycodone Naproxen — — Caffeine Naltrexone — 408 Oxycodone Naproxen— — Caffeine — Niacin 409 Oxycodone Naproxen — — — Naltrexone Niacin 410Oxycodone — Promethazine Butalbital Modafinil — — 411 Oxycodone —Promethazine Butalbital Caffeine — — 412 Oxycodone — PromethazineButalbital — Naltrexone — 413 Oxycodone — Promethazine Butalbital — —Niacin 414 Oxycodone — Promethazine — Modafinil Naltrexone — 415Oxycodone — Promethazine — Caffeine Naltrexone — 416 Oxycodone —Promethazine — Modafinil — Niacin 417 Oxycodone — Promethazine —Caffeine — Niacin 418 Oxycodone — Promethazine — — Naltrexone Niacin 419Oxycodone — — Butalbital Modafinil Naltrexone — 420 Oxycodone — —Butalbital Caffeine Naltrexone — 421 Oxycodone — — Butalbital Modafinil— Niacin 422 Oxycodone — — Butalbital Caffeine — Niacin 423 Oxycodone —— Butalbital — Naltrexone Niacin 424 Oxycodone — — — ModafinilNaltrexone Niacin 425 Oxycodone — — — Caffeine Naltrexone Niacin 426Oxycodone Naproxen Promethazine Butalbital Modafinil — — 427 OxycodoneNaproxen Promethazine Butalbital Caffeine — — 428 Oxycodone NaproxenPromethazine Butalbital — Naltrexone — 429 Oxycodone NaproxenPromethazine Butalbital — — Niacin 430 Oxycodone Naproxen Promethazine —Modafinil Naltrexone — 431 Oxycodone Naproxen Promethazine — CaffeineNaltrexone — 432 Oxycodone Naproxen Promethazine — Modafinil — Niacin433 Oxycodone Naproxen Promethazine — Caffeine — Niacin 434 OxycodoneNaproxen Promethazine — — Naltrexone Niacin 435 Oxycodone Naproxen —Butalbital Modafinil Naltrexone — 436 Oxycodone Naproxen — ButalbitalCaffeine Naltrexone — 437 Oxycodone Naproxen — Butalbital Modafinil —Niacin 438 Oxycodone Naproxen — Butalbital Caffeine — Niacin 439Oxycodone Naproxen — Butalbital — Naltrexone Niacin 440 OxycodoneNaproxen — — Modafinil Naltrexone Niacin 441 Oxycodone Naproxen — —Caffeine Naltrexone Niacin 442 Oxycodone — Promethazine ButalbitalModafinil Naltrexone — 443 Oxycodone — Promethazine Butalbital CaffeineNaltrexone — 444 Oxycodone — Promethazine Butalbital Modafinil — Niacin445 Oxycodone — Promethazine Butalbital Caffeine — Niacin 446 Oxycodone— Promethazine Butalbital — Naltrexone Niacin 447 Oxycodone — —Butalbital Caffeine Naltrexone Niacin 448 Oxycodone NaproxenPromethazine Butalbital Modafinil Naltrexone — 449 Oxycodone NaproxenPromethazine Butalbital Caffeine Naltrexone — 450 Oxycodone NaproxenPromethazine Butalbital Modafinil — Niacin 451 Oxycodone NaproxenPromethazine Butalbital Caffeine — Niacin 452 Oxycodone — PromethazineButalbital Modafinil Naltrexone Niacin 453 Oxycodone — PromethazineButalbital Caffeine Naltrexone Niacin 454 Oxycodone Naproxen —Butalbital Modafinil Naltrexone Niacin 455 Oxycodone Naproxen —Butalbital Caffeine Naltrexone Niacin 456 Oxycodone NaproxenPromethazine — Modafinil Naltrexone Niacin 457 Oxycodone NaproxenPromethazine — Caffeine Naltrexone Niacin 458 Oxycodone NaproxenPromethazine Butalbital — Naltrexone Niacin 459 Oxycodone NaproxenPromethazine Butalbital Modafinil Naltrexone Niacin 460 OxycodoneNaproxen Promethazine Butalbital Caffeine Naltrexone Niacin 461Oxycodone Ibuprofen — — — — — 462 Oxycodone — Promethazine — — — — 463Oxycodone — — Butalbital — — — 464 Oxycodone — — — Modafinil — — 465Oxycodone — — — Caffeine —- —- 466 Oxycodone — — — — Naltrexone — 467Oxycodone — — — — — Niacin 468 Oxycodone Ibuprofen Promethazine — — — —469 Oxycodone Ibuprofen — Butalbital — — — 470 Oxycodone Ibuprofen — —Modafinil — — 471 Oxycodone Ibuprofen — — Caffeine — — 472 OxycodoneIbuprofen — — — Naltrexone — 473 Oxycodone Ibuprofen — — — — Niacin 474Oxycodone — Promethazine Butalbital — — — 475 Oxycodone — Promethazine —Modafinil — — 476 Oxycodone — Promethazine — Caffeine — — 477 Oxycodone— Promethazine — — Naltrexone — 478 Oxycodone — Promethazine — — —Niacin 479 Oxycodone — — Butalbital Modafinil — — 480 Oxycodone — —Butalbital Caffeine — — 481 Oxycodone — — Butalbital — Naltrexone — 482Oxycodone — — Butalbital — — Niacin 483 Oxycodone — — — ModafinilNaltrexone — 484 Oxycodone — — — Caffeine Naltrexone — 485 Oxycodone — —— Modafinil — Niacin 486 Oxycodone — — — Caffeine — Niacin 487 Oxycodone— — — — Naltrexone Niacin 488 Oxycodone Ibuprofen PromethazineButalbital — — — 489 Oxycodone Ibuprofen Promethazine — Modafinil — —490 Oxycodone Ibuprofen Promethazine — Caffeine — — 491 OxycodoneIbuprofen Promethazine — — Naltrexone — 492 Oxycodone IbuprofenPromethazine — — — Niacin 493 Oxycodone Ibuprofen — Butalbital Modafinil— — 494 Oxycodone Ibuprofen — Butalbital Caffeine — — 495 OxycodoneIbuprofen — Butalbital — Naltrexone — 496 Oxycodone Ibuprofen —Butalbital — — Niacin 497 Oxycodone Ibuprofen — — Modafinil Naltrexone —498 Oxycodone Ibuprofen — — Modafinil — Niacin 499 Oxycodone Ibuprofen —— Caffeine Naltrexone — 500 Oxycodone Ibuprofen — — Caffeine — Niacin501 Oxycodone Ibuprofen — — — Naltrexone Niacin 502 Oxycodone —Promethazine Butalbital Modafinil — — 503 Oxycodone — PromethazineButalbital Caffeine — — 504 Oxycodone — Promethazine Butalbital —Naltrexone — 505 Oxycodone — Promethazine Butalbital — — Niacin 506Oxycodone — Promethazine — Modafinil Naltrexone — 507 Oxycodone —Promethazine — Caffeine Naltrexone — 508 Oxycodone — Promethazine —Modafinil — Niacin 509 Oxycodone — Promethazine — Caffeine — Niacin 510Oxycodone — Promethazine — — Naltrexone Niacin 511 Oxycodone — —Butalbital Modafinil Naltrexone — 512 Oxycodone — — Butalbital CaffeineNaltrexone — 513 Oxycodone — — Butalbital Modafinil — Niacin 514Oxycodone — — Butalbital Caffeine — Niacin 515 Oxycodone — — Butalbital— Naltrexone Niacin 516 Oxycodone — — — Modafinil Naltrexone Niacin 517Oxycodone — — — Caffeine Naltrexone Niacin 518 Oxycodone IbuprofenPromethazine Butalbital Modafinil — — 519 Oxycodone IbuprofenPromethazine Butalbital Caffeine — — 520 Oxycodone IbuprofenPromethazine Butalbital — Naltrexone — 521 Oxycodone IbuprofenPromethazine Butalbital — — Niacin 522 Oxycodone Ibuprofen Promethazine— Modafinil Naltrexone — 523 Oxycodone Ibuprofen Promethazine — CaffeineNaltrexone — 524 Oxycodone Ibuprofen Promethazine — Modafinil — Niacin525 Oxycodone Ibuprofen Promethazine — Caffeine — Niacin 526 OxycodoneIbuprofen Promethazine — — Naltrexone Niacin 527 Oxycodone Ibuprofen —Butalbital Modafinil Naltrexone — 528 Oxycodone Ibuprofen — ButalbitalCaffeine Naltrexone — 529 Oxycodone Ibuprofen — Butalbital Modafinil —Niacin 530 Oxycodone Ibuprofen — Butalbital Caffeine — Niacin 531Oxycodone Ibuprofen — Butalbital — Naltrexone Niacin 532 OxycodoneIbuprofen — — Modafinil Naltrexone Niacin 533 Oxycodone Ibuprofen — —Caffeine Naltrexone Niacin 534 Oxycodone — Promethazine ButalbitalModafinil Naltrexone — 535 Oxycodone — Promethazine Butalbital CaffeineNaltrexone — 536 Oxycodone — Promethazine Butalbital Modafinil — Niacin537 Oxycodone — Promethazine Butalbital Caffeine — Niacin 538 Oxycodone— Promethazine Butalbital — Naltrexone Niacin 539 Oxycodone — —Butalbital Caffeine Naltrexone Niacin 540 Oxycodone IbuprofenPromethazine Butalbital Modafinil Naltrexone — 541 Oxycodone IbuprofenPromethazine Butalbital Caffeine Naltrexone — 542 Oxycodone IbuprofenPromethazine Butalbital Modafinil — Niacin 543 Oxycodone IbuprofenPromethazine Butalbital Caffeine — Niacin 544 Oxycodone — PromethazineButalbital Modafinil Naltrexone Niacin 545 Oxycodone — PromethazineButalbital Caffeine Naltrexone Niacin 546 Oxycodone Ibuprofen —Butalbital Modafinil Naltrexone Niacin 547 Oxycodone Ibuprofen —Butalbital Caffeine Naltrexone Niacin 548 Oxycodone IbuprofenPromethazine — Modafinil Naltrexone Niacin 549 Oxycodone IbuprofenPromethazine — Caffeine Naltrexone Niacin 550 Oxycodone IbuprofenPromethazine Butalbital — Naltrexone Niacin 551 Oxycodone IbuprofenPromethazine Butalbital Modafinil Naltrexone Niacin 552 OxycodoneIbuprofen Promethazine Butalbital Caffeine Naltrexone Niacin 553Propoxyphene Acetaminophen — — — — — 554 Propoxyphene — Promethazine — —— — 555 Propoxyphene — — Butalbital — — — 556 Propoxyphene — — —Modafmil — — 557 Propoxyphene — — — Caffeine — — 558 Propoxyphene — — —— Naltrexone — 559 Propoxyphene — — — — — Niacin 560 PropoxypheneAcetaminophen Promethazine — — — — 561 Propoxyphene Acetaminophen —Butalbital — — — 562 Propoxyphene Acetaminophen — — Modafmil — — 563Propoxyphene Acetaminophen — — Caffeine — — 564 PropoxypheneAcetaminophen — — — Naltrexone — 565 Propoxyphene Acetaminophen — — — —Niacin 566 Propoxyphene — Promethazine Butalbital — — — 567 Propoxyphene— Promethazine — Modafmil — — 568 Propoxyphene — Promethazine — Caffeine— — 569 Propoxyphene — Promethazine — — Naltrexone — 570 Propoxyphene —Promethazine — — — Niacin 571 Propoxyphene — — Butalbital Modafinil — —572 Propoxyphene — — Butalbital Caffeine — — 573 Propoxyphene — —Butalbital — Naltrexone — 574 Propoxyphene — — Butalbital — — Niacin 575Propoxyphene — — — Modafinil Naltrexone — 576 Propoxyphene — — —Caffeine Naltrexone — 577 Propoxyphene — — — Modafinil — Niacin 578Propoxyphene — — — Caffeine — Niacin 579 Propoxyphene — — — — NaltrexoneNiacin 580 Propoxyphene Acetaminophen Promethazine Butalbital — — — 581Propoxyphene Acetaminophen Promethazine — Modafinil — — 582 PropoxypheneAcetaminophen Promethazine — Caffeine — — 583 Propoxyphene AcetaminophenPromethazine — — Naltrexone — 584 Propoxyphene AcetaminophenPromethazine — — — Niacin 585 Propoxyphene Acetaminophen — ButalbitalModafinil — — 586 Propoxyphene Acetaminophen — Butalbital Caffeine — —587 Propoxyphene Acetaminophen — Butalbital — Naltrexone — 588Propoxyphene Acetaminophen — Butalbital — — Niacin 589 PropoxypheneAcetaminophen — — Modafinil Naltrexone — 590 Propoxyphene Acetaminophen— — Modafinil — Niacin 591 Propoxyphene Acetaminophen — — CaffeineNaltrexone — 592 Propoxyphene Acetaminophen — — Caffeine — Niacin 593Propoxyphene Acetaminophen — — — Naltrexone Niacin 594 Propoxyphene —Promethazine Butalbital Modafinil — — 595 Propoxyphene — PromethazineButalbital Caffeine — — 596 Propoxyphene — Promethazine Butalbital —Naltrexone — 597 Propoxyphene — Promethazine Butalbital — — Niacin 598Propoxyphene — Promethazine — Modafinil Naltrexone — 599 Propoxyphene —Promethazine — Caffeine Naltrexone — 600 Propoxyphene — Promethazine —Modafinil — Niacin 601 Propoxyphene — Promethazine — Caffeine — Niacin602 Propoxyphene — Promethazine — — Naltrexone Niacin 603 Propoxyphene —— Butalbital Modafinil Naltrexone — 604 Propoxyphene — — ButalbitalCaffeine Naltrexone — 605 Propoxyphene — — Butalbital Modafinil — Niacin606 Propoxyphene — — Butalbital Caffeine — Niacin 607 Propoxyphene — —Butalbital — Naltrexone Niacin 608 Propoxyphene — — — ModafinilNaltrexone Niacin 609 Propoxyphene — — — Caffeine Naltrexone Niacin 610Propoxyphene Acetaminophen Promethazine Butalbital Modafinil — — 611Propoxyphene Acetaminophen Promethazine Butalbital Caffeine — — 612Propoxyphene Acetaminophen Promethazine Butalbital — Naltrexone — 613Propoxyphene Acetaminophen Promethazine Butalbital — — Niacin 614Propoxyphene Acetaminophen Promethazine — Modafinil Naltrexone — 615Propoxyphene Acetaminophen Promethazine — Caffeine Naltrexone — 616Propoxyphene Acetaminophen Promethazine — Modafinil — Niacin 617Propoxyphene Acetaminophen Promethazine — Caffeine — Niacin 618Propoxyphene Acetaminophen Promethazine — — Naltrexone Niacin 619Propoxyphene Acetaminophen — Butalbital Modafinil Naltrexone — 620Propoxyphene Acetaminophen — Butalbital Caffeine Naltrexone — 621Propoxyphene Acetaminophen — Butalbital Modafinil — Niacin 622Propoxyphene Acetaminophen — Butalbital Caffeine — Niacin 623Propoxyphene Acetaminophen — Butalbital — Naltrexone Niacin 624Propoxyphene Acetaminophen — — Modafinil Naltrexone Niacin 625Propoxyphene Acetaminophen — — Caffeine Naltrexone Niacin 626Propoxyphene — Promethazine Butalbital Modafinil Naltrexone — 627Propoxyphene — Promethazine Butalbital Caffeine Naltrexone — 628Propoxyphene — Promethazine Butalbital Modafinil — Niacin 629Propoxyphene — Promethazine Butalbital Caffeine — Niacin 630Propoxyphene — Promethazine Butalbital — Naltrexone Niacin 631Propoxyphene — — Butalbital Caffeine Naltrexone Niacin 632 PropoxypheneAcetaminophen Promethazine Butalbital Modafinil Naltrexone — 633Propoxyphene Acetaminophen Promethazine Butalbital Caffeine Naltrexone —634 Propoxyphene Acetaminophen Promethazine Butalbital Modafinil —Niacin 635 Propoxyphene Acetaminophen Promethazine Butalbital Caffeine —Niacin 636 Propoxyphene — Promethazine Butalbital Modafinil NaltrexoneNiacin 637 Propoxyphene — Promethazine Butalbital Caffeine NaltrexoneNiacin 638 Propoxyphene Acetaminophen — Butalbital Modafmil NaltrexoneNiacin 639 Propoxyphene Acetaminophen — Butalbital Caffeine NaltrexoneNiacin 640 Propoxyphene Acetaminophen Promethazine — ModafinilNaltrexone Niacin 641 Propoxyphene Acetaminophen Promethazine — CaffeineNaltrexone Niacin 642 Propoxyphene Acetaminophen Promethazine Butalbital— Naltrexone Niacin 643 Propoxyphene Acetaminophen PromethazineButalbital Modafinil Naltrexone Niacin 644 Propoxyphene AcetaminophenPromethazine Butalbital Caffeine Naltrexone Niacin 645 PropoxypheneNaproxen — — — — — 646 Propoxyphene — Promethazine — — — — 647Propoxyphene — — Butalbital — — — 648 Propoxyphene — — — Modafinil — —649 Propoxyphene — — — Caffeine — — 650 Propoxyphene — — — — Naltrexone— 651 Propoxyphene — — — — — Niacin 652 Propoxyphene NaproxenPromethazine — — — — 653 Propoxyphene Naproxen — Butalbital — — — 654Propoxyphene Naproxen — — Modafinil — — 655 Propoxyphene Naproxen — —Caffeine — — 656 Propoxyphene Naproxen — — — Naltrexone — 657Propoxyphene Naproxen — — — — Niacin 658 Propoxyphene — PromethazineButalbital — — — 659 Propoxyphene — Promethazine — Modafinil — — 660Propoxyphene — Promethazine — Caffeine — — 661 Propoxyphene —Promethazine — — Naltrexone — 662 Propoxyphene — Promethazine — — —Niacin 663 Propoxyphene — — Butalbital Modafinil — — 664 Propoxyphene —— Butalbital Caffeine — — 665 Propoxyphene — — Butalbital — Naltrexone —666 Propoxyphene — — Butalbital — — Niacin 667 Propoxyphene — — —Modafinil Naltrexone — 668 Propoxyphene — — — Caffeine Naltrexone — 669Propoxyphene — — — Modafinil — Niacin 670 Propoxyphene — — — Caffeine —Niacin 671 Propoxyphene — — — — Naltrexone Niacin 672 PropoxypheneNaproxen Promethazine Butalbital — — — 673 Propoxyphene NaproxenPromethazine — Modafinil — — 674 Propoxyphene Naproxen Promethazine —Caffeine — — 675 Propoxyphene Naproxen Promethazine — — Naltrexone — 676Propoxyphene Naproxen Promethazine — — — Niacin 677 PropoxypheneNaproxen — Butalbital Modafinil — — 678 Propoxyphene Naproxen —Butalbital Caffeine — — 679 Propoxyphene Naproxen — Butalbital —Naltrexone — 680 Propoxyphene Naproxen — Butalbital — — Niacin 681Propoxyphene Naproxen — — Modafinil Naltrexone — 682 PropoxypheneNaproxen — — Modafinil — Niacin 683 Propoxyphene Naproxen — — CaffeineNaltrexone — 684 Propoxyphene Naproxen — — Caffeine — Niacin 685Propoxyphene Naproxen — — — Naltrexone Niacin 686 Propoxyphene —Promethazine Butalbital Modafinil — — 687 Propoxyphene — PromethazineButalbital Caffeine — — 688 Propoxyphene — Promethazine Butalbital —Naltrexone — 689 Propoxyphene — Promethazine Butalbital — — Niacin 690Propoxyphene — Promethazine — Modafinil Naltrexone — 691 Propoxyphene —Promethazine — Caffeine Naltrexone — 692 Propoxyphene — Promethazine —Modafinil — Niacin 693 Propoxyphene — Promethazine — Caffeine — Niacin694 Propoxyphene — Promethazine — — Naltrexone Niacin 695 Propoxyphene —— Butalbital Modafinil Naltrexone — 696 Propoxyphene — — ButalbitalCaffeine Naltrexone — 697 Propoxyphene — — Butalbital Modafinil — Niacin698 Propoxyphene — — Butalbital Caffeine — Niacin 699 Propoxyphene — —Butalbital — Naltrexone Niacin 700 Propoxyphene — — — ModafinilNaltrexone Niacin 701 Propoxyphene — — — Caffeine Naltrexone Niacin 702Propoxyphene Naproxen Promethazine Butalbital Modafinil — — 703Propoxyphene Naproxen Promethazine Butalbital Caffeine — — 704Propoxyphene Naproxen Promethazine Butalbital — Naltrexone — 705Propoxyphene Naproxen Promethazine Butalbital — — Niacin 706Propoxyphene Naproxen Promethazine — Modafinil Naltrexone — 707Propoxyphene Naproxen Promethazine — Caffeine Naltrexone — 708Propoxyphene Naproxen Promethazine — Modafinil — Niacin 709 PropoxypheneNaproxen Promethazine — Caffeine — Niacin 710 Propoxyphene NaproxenPromethazine — — Naltrexone Niacin 711 Propoxyphene Naproxen —Butalbital Modafinil Naltrexone — 712 Propoxyphene Naproxen — ButalbitalCaffeine Naltrexone — 713 Propoxyphene Naproxen — Butalbital Modafinil —Niacin 714 Propoxyphene Naproxen — Butalbital Caffeine — Niacin 715Propoxyphene Naproxen — Butalbital — Naltrexone Niacin 716 PropoxypheneNaproxen — — Modafinil Naltrexone Niacin 717 Propoxyphene Naproxen — —Caffeine Naltrexone Niacin 718 Propoxyphene — Promethazine ButalbitalModafinil Naltrexone — 719 Propoxyphene — Promethazine ButalbitalCaffeine Naltrexone — 720 Propoxyphene — Promethazine ButalbitalModafmil — Niacin 721 Propoxyphene — Promethazine Butalbital Caffeine —Niacin 722 Propoxyphene — Promethazine Butalbital — Naltrexone Niacin723 Propoxyphene — — Butalbital Caffeine Naltrexone Niacin 724Propoxyphene Naproxen Promethazine Butalbital Modafmil Naltrexone — 725Propoxyphene Naproxen Promethazine Butalbital Caffeine Naltrexone — 726Propoxyphene Naproxen Promethazine Butalbital Modafmil —- Niacin 727Propoxyphene Naproxen Promethazine Butalbital Caffeine — Niacin 728Propoxyphene — Promethazine Butalbital Modafinil Naltrexone Niacin 729Propoxyphene — Promethazine Butalbital Caffeine Naltrexone Niacin 730Propoxyphene Naproxen — Butalbital Modafinil Naltrexone Niacin 731Propoxyphene Naproxen — Butalbital Caffeine Naltrexone Niacin 732Propoxyphene Naproxen Promethazine — Modafinil Naltrexone Niacin 733Propoxyphene Naproxen Promethazine — Caffeine Naltrexone Niacin 734Propoxyphene Naproxen Promethazine Butalbital — Naltrexone Niacin 735Propoxyphene Naproxen Promethazine Butalbital Modafinil NaltrexoneNiacin 736 Propoxyphene Naproxen Promethazine Butalbital CaffeineNaltrexone Niacin 737 Propoxyphene Ibuprofen — — — — — 738 Propoxyphene— Promethazine — — — — 739 Propoxyphene — — Butalbital — — — 740Propoxyphene — — — Modafinil — — 741 Propoxyphene — — — Caffeine — — 742Propoxyphene — — — — Naltrexone — 743 Propoxyphene — — — — — Niacin 744Propoxyphene Ibuprofen Promethazine — — — — 745 Propoxyphene Ibuprofen —Butalbital — — — 746 Propoxyphene Ibuprofen — — Modafinil — — 747Propoxyphene Ibuprofen — — Caffeine — — 748 Propoxyphene Ibuprofen — — —Naltrexone — 749 Propoxyphene Ibuprofen — — — — Niacin 750 Propoxyphene— Promethazine Butalbital — — — 751 Propoxyphene — Promethazine —Modafinil — — 752 Propoxyphene — Promethazine — Caffeine — — 753Propoxyphene — Promethazine — — Naltrexone — 754 Propoxyphene —Promethazine — — — Niacin 755 Propoxyphene — — Butalbital Modafinil — —756 Propoxyphene — — Butalbital Caffeine — — 757 Propoxyphene — —Butalbital — Naltrexone — 758 Propoxyphene — — Butalbital — — Niacin 759Propoxyphene — — — Modafinil Naltrexone — 760 Propoxyphene — — —Caffeine Naltrexone — 761 Propoxyphene — — — Modafinil — Niacin 762Propoxyphene — — — Caffeine — Niacin 763 Propoxyphene — — — — NaltrexoneNiacin 764 Propoxyphene Ibuprofen Promethazine Butalbital — — — 765Propoxyphene Ibuprofen Promethazine — Modafinil — — 766 PropoxypheneIbuprofen Promethazine — Caffeine — — 767 Propoxyphene IbuprofenPromethazine — — Naltrexone — 768 Propoxyphene Ibuprofen Promethazine —— — Niacin 769 Propoxyphene Ibuprofen — Butalbital Modafinil — — 770Propoxyphene Ibuprofen — Butalbital Caffeine — — 771 PropoxypheneIbuprofen — Butalbital — Naltrexone — 772 Propoxyphene Ibuprofen —Butalbital — — Niacin 773 Propoxyphene Ibuprofen — — ModafinilNaltrexone — 774 Propoxyphene Ibuprofen — — Modafinil — Niacin 775Propoxyphene Ibuprofen — — Caffeine Naltrexone — 776 PropoxypheneIbuprofen — — Caffeine — Niacin 111 Propoxyphene Ibuprofen — — —Naltrexone Niacin 778 Propoxyphene — Promethazine Butalbital Modafinil —— 779 Propoxyphene — Promethazine Butalbital Caffeine — — 780Propoxyphene — Promethazine Butalbital — Naltrexone — 781 Propoxyphene —Promethazine Butalbital — — Niacin 782 Propoxyphene — Promethazine —Modafinil Naltrexone — 783 Propoxyphene — Promethazine — CaffeineNaltrexone — 784 Propoxyphene — Promethazine — Modafinil — Niacin 785Propoxyphene — Promethazine — Caffeine — Niacin 786 Propoxyphene —Promethazine — — Naltrexone Niacin 787 Propoxyphene — — ButalbitalModafinil Naltrexone — 788 Propoxyphene — — Butalbital CaffeineNaltrexone — 789 Propoxyphene — — Butalbital Modafinil — Niacin 790Propoxyphene — — Butalbital Caffeine — Niacin 791 Propoxyphene — —Butalbital — Naltrexone Niacin 792 Propoxyphene — — — ModafinilNaltrexone Niacin 793 Propoxyphene — — — Caffeine Naltrexone Niacin 794Propoxyphene Ibuprofen Promethazine Butalbital Modafinil — — 795Propoxyphene Ibuprofen Promethazine Butalbital Caffeine — — 796Propoxyphene Ibuprofen Promethazine Butalbital — Naltrexone — 797Propoxyphene Ibuprofen Promethazine Butalbital — — Niacin 798Propoxyphene Ibuprofen Promethazine — Modafinil Naltrexone — 799Propoxyphene Ibuprofen Promethazine — Caffeine Naltrexone — 800Propoxyphene Ibuprofen Promethazine — Modafinil — Niacin 801Propoxyphene Ibuprofen Promethazine — Caffeine — Niacin 802 PropoxypheneIbuprofen Promethazine — — Naltrexone Niacin 803 Propoxyphene Ibuprofen— Butalbital Modafinil Naltrexone — 804 Propoxyphene Ibuprofen —Butalbital Caffeine Naltrexone — 805 Propoxyphene Ibuprofen — ButalbitalModafinil — Niacin 806 Propoxyphene Ibuprofen — Butalbital Caffeine —Niacin 807 Propoxyphene Ibuprofen — Butalbital — Naltrexone Niacin 808Propoxyphene Ibuprofen — — Modafinil Naltrexone Niacin 809 PropoxypheneIbuprofen — — Caffeine Naltrexone Niacin 810 Propoxyphene — PromethazineButalbital Modafinil Naltrexone — 811 Propoxyphene — PromethazineButalbital Caffeine Naltrexone — 812 Propoxyphene — PromethazineButalbital Modafinil — Niacin 813 Propoxyphene — Promethazine ButalbitalCaffeine — Niacin 814 Propoxyphene — Promethazine Butalbital —Naltrexone Niacin 815 Propoxyphene — — Butalbital Caffeine NaltrexoneNiacin 816 Propoxyphene Ibuprofen Promethazine Butalbital ModafinilNaltrexone — 817 Propoxyphene Ibuprofen Promethazine Butalbital CaffeineNaltrexone — 818 Propoxyphene Ibuprofen Promethazine ButalbitalModafinil — Niacin 819 Propoxyphene Ibuprofen Promethazine ButalbitalCaffeine — Niacin 820 Propoxyphene — Promethazine Butalbital ModafinilNaltrexone Niacin 821 Propoxyphene — Promethazine Butalbital CaffeineNaltrexone Niacin 822 Propoxyphene Ibuprofen — Butalbital ModafinilNaltrexone Niacin 823 Propoxyphene Ibuprofen — Butalbital CaffeineNaltrexone Niacin 824 Propoxyphene Ibuprofen Promethazine — ModafinilNaltrexone Niacin 825 Propoxyphene Ibuprofen Promethazine — CaffeineNaltrexone Niacin 826 Propoxyphene Ibuprofen Promethazine Butalbital —Naltrexone Niacin 827 Propoxyphene Ibuprofen Promethazine ButalbitalModafinil Naltrexone Niacin 828 Propoxyphene Ibuprofen PromethazineButalbital Caffeine Naltrexone Niacin 829 Propoxyphene Ibuprofen — — — —— 830 — Acetaminophen — — Modafinil — — 831 — Acetaminophen — — Caffeine— — 832 — Ibuprofen — — Modafinil — — 833 — Ibuprofen — — Caffeine — —834 — Naproxen — — Modafinil — — 835 — Naproxen — — Caffeine — — 836 —Acetaminophen — Butalbital Modafinil — — 837 — Acetaminophen —Butalbital Caffeine — — 838 — Ibuprofen — Butalbital Modafinil — — 839 —Ibuprofen — Butalbital Caffeine — — 840 — Naproxen — ButalbitalModafinil — — 841 — Naproxen — Butalbital Caffeine — — Note: — indicatesthat the respective agent is absent from a particular composition.

TABLE 2 Multi-drug Compositions Composition No. Triptan Antiemetic agent842 naratriptan promethazine 843 naratriptan aprepitant 844 naratriptandronabinol 845 naratriptan perphenazine 846 naratriptan palonosetron 847naratriptan trimethyobenzamide 848 naratriptan metoclopromide 849naratriptan domperidone 850 naratriptan prochlorperazine 851 naratriptanpromethazine 852 naratriptan chlorpromazine 853 naratriptantrimethobenzamide 854 naratriptan ondansetron 855 naratriptangranisetron 856 naratriptan hydroxyzine 857 naratriptan acetylleucine858 naratriptan monoethanolamine 859 naratriptan alizapride 860naratriptan azasetron 861 naratriptan benzquinamide 862 naratriptanbietanautine 863 naratriptan bromopride 864 naratriptan buclizine 865naratriptan clebopride 866 naratriptan cyclizine 867 naratriptandimenhydrinate 868 naratriptan diphenidol 869 naratriptan dolasetron 870naratriptan meclizine 871 naratriptan methallatal 872 naratriptanmetopimazine 873 naratriptan nabilone 874 naratriptan oxyperndyl 875naratriptan pipamazine 876 naratriptan scopolamine 877 naratriptansulpiride 878 naratriptan tetrahydrocannabinol 879 naratriptanthiethylperazine 880 naratriptan thioproperazine 881 naratriptantropisetron 882 naratriptan droperidol 883 naratriptan haloperidol 884naratriptan prochloperazine 885 naratriptan metoclopramide 886naratriptan diphenhydramine 887 naratriptan cannabis 888 naratriptanmidazolam 889 naratriptan lorazepam 890 naratriptan hyoscine 891naratriptan dexamethasone 892 naratriptan emetrol 893 naratriptanpropofol 894 almotriptan promethazine 895 almotriptan aprepitant 896almotriptan dronabinol 897 almotriptan perphenazine 898 almotriptanpalonosetron 899 almotriptan trimethyobenzamide 900 almotriptanmetoclopromide 901 almotriptan domperidone 902 almotriptanprochlorperazine 903 almotriptan promethazine 904 almotriptanchlorpromazine 905 almotriptan trimethobenzamide 906 almotriptanondansetron 907 almotriptan granisetron 908 almotriptan hydroxyzine 909almotriptan acetylleucine 910 almotriptan monoethanolamine 911almotriptan alizapride 912 almotriptan azasetron 913 almotriptanbenzquinamide 914 almotriptan bietanautine 915 almotriptan bromopride916 almotriptan buclizine 917 almotriptan clebopride 918 almotriptancyclizine 919 almotriptan dimenhydrinate 920 almotriptan diphenidol 921almotriptan dolasetron 922 almotriptan meclizine 923 almotriptanmethallatal 924 almotriptan metopimazine 925 almotriptan nabilone 926almotriptan oxyperndyl 927 almotriptan pipamazine 928 almotriptanscopolamine 929 almotriptan sulpiride 930 almotriptantetrahydrocannabinol 931 almotriptan thiethylperazine 932 almotriptanthioproperazine 933 almotriptan tropisetron 934 almotriptan droperidol935 almotriptan haloperidol 936 almotriptan prochloperazine 937almotriptan metoclopramide 938 almotriptan diphenhydramine 939almotriptan cannabis 940 almotriptan midazolam 941 almotriptan lorazepam942 almotriptan hyoscine 943 almotriptan dexamethasone 944 almotriptanemetrol 945 almotriptan propofol 946 sumatriptan promethazine 947sumatriptan aprepitant 948 sumatriptan dronabinol 949 sumatriptanperphenazine 950 sumatriptan palonosetron 951 sumatriptantrimethyobenzamide 952 sumatriptan metoclopromide 953 sumatriptandomperidone 954 sumatriptan prochlorperazine 955 sumatriptanpromethazine 956 sumatriptan chlorpromazine 957 sumatriptantrimethobenzamide 958 sumatriptan ondansetron 959 sumatriptangranisetron 960 sumatriptan hydroxyzine 961 sumatriptan acetylleucine962 sumatriptan monoethanolamine 963 sumatriptan alizapride 964sumatriptan azasetron 965 sumatriptan benzquinamide 966 sumatriptanbietanautine 967 sumatriptan bromopride 968 sumatriptan buclizine 969sumatriptan clebopride 970 sumatriptan cyclizine 971 sumatriptandimenhydrinate 972 sumatriptan diphenidol 973 sumatriptan dolasetron 974sumatriptan meclizine 975 sumatriptan methallatal 976 sumatriptanmetopimazine 977 sumatriptan nabilone 978 sumatriptan oxyperndyl 979sumatriptan pipamazine 980 sumatriptan scopolamine 981 sumatriptansulpiride 982 sumatriptan tetrahydrocannabinol 983 sumatriptanthiethylperazine 984 sumatriptan thioproperazine 985 sumatriptantropisetron 986 sumatriptan droperidol 987 sumatriptan haloperidol 988sumatriptan prochloperazine 989 sumatriptan metoclopramide 990sumatriptan diphenhydramine 991 sumatriptan cannabis 992 sumatriptanmidazolam 993 sumatriptan lorazepam 994 sumatriptan hyoscine 995sumatriptan dexamethasone 996 sumatriptan emetrol 997 sumatriptanpropofol 998 zolmitriptan promethazine 999 zolmitriptan aprepitant 1000zolmitriptan dronabinol 1001 zolmitriptan perphenazine 1002 zolmitriptanpalonosetron 1003 zolmitriptan trimethyobenzamide 1004 zolmitriptanmetoclopromide 1005 zolmitriptan domperidone 1006 zolmitriptanprochlorperazine 1007 zolmitriptan promethazine 1008 zolmitriptanchlorpromazine 1009 zolmitriptan trimethobenzamide 1010 zolmitriptanondansetron 1011 zolmitriptan granisetron 1012 zolmitriptan hydroxyzine1013 zolmitriptan acetylleucine 1014 zolmitriptan monoethanolamine 1015zolmitriptan alizapride 1016 zolmitriptan azasetron 1017 zolmitriptanbenzquinamide 1018 zolmitriptan bietanautine 1019 zolmitriptanbromopride 1020 zolmitriptan buclizine 1021 zolmitriptan clebopride 1022zolmitriptan cyclizine 1023 zolmitriptan dimenhydrinate 1024zolmitriptan diphenidol 1025 zolmitriptan dolasetron 1026 zolmitriptanmeclizine 1027 zolmitriptan methallatal 1028 zolmitriptan metopimazine1029 zolmitriptan nabilone 1030 zolmitriptan oxyperndyl 1031zolmitriptan pipamazine 1032 zolmitriptan scopolamine 1033 zolmitriptansulpiride 1034 zolmitriptan tetrahydrocannabinol 1035 zolmitriptanthiethylperazine 1036 zolmitriptan thioproperazine 1037 zolmitriptantropisetron 1038 zolmitriptan droperidol 1039 zolmitriptan haloperidol1040 zolmitriptan prochloperazine 1041 zolmitriptan metoclopramide 1042zolmitriptan diphenhydramine 1043 zolmitriptan cannabis 1044zolmitriptan midazolam 1045 zolmitriptan lorazepam 1046 zolmitriptanhyoscine 1047 zolmitriptan dexamethasone 1048 zolmitriptan emetrol 1049zolmitriptan propofol 1050 eletriptan promethazine 1051 eletriptanaprepitant 1052 eletriptan dronabinol 1053 eletriptan perphenazine 1054eletriptan palonosetron 1055 eletriptan trimethyobenzamide 1056eletriptan metoclopromide 1057 eletriptan domperidone 1058 eletriptanprochlorperazine 1059 eletriptan promethazine 1060 eletriptanchlorpromazine 1061 eletriptan trimethobenzamide 1062 eletriptanondansetron 1063 eletriptan granisetron 1064 eletriptan hydroxyzine 1065eletriptan acetylleucine 1066 eletriptan monoethanolamine 1067eletriptan alizapride 1068 eletriptan azasetron 1069 eletriptanbenzquinamide 1070 eletriptan bietanautine 1071 eletriptan bromopride1072 eletriptan buclizine 1073 eletriptan clebopride 1074 eletriptancyclizine 1075 eletriptan dimenhydrinate 1076 eletriptan diphenidol 1077eletriptan dolasetron 1078 eletriptan meclizine 1079 eletriptanmethallatal 1080 eletriptan metopimazine 1081 eletriptan nabilone 1082eletriptan oxyperndyl 1083 eletriptan pipamazine 1084 eletriptanscopolamine 1085 eletriptan sulpiride 1086 eletriptantetrahydrocannabinol 1087 eletriptan thiethylperazine 1088 eletriptanthioproperazine 1089 eletriptan tropisetron 1090 eletriptan droperidol1091 eletriptan haloperidol 1092 eletriptan prochloperazine 1093eletriptan metoclopramide 1094 eletriptan diphenhydramine 1095eletriptan cannabis 1096 eletriptan midazolam 1097 eletriptan lorazepam1098 eletriptan hyoscine 1099 eletriptan dexamethasone 1100 eletriptanemetrol 1101 eletriptan propofol 1102 frovatriptan promethazine 1103frovatriptan aprepitant 1104 frovatriptan dronabinol 1105 frovatriptanperphenazine 1106 frovatriptan palonosetron 1107 frovatriptantrimethyobenzamide 1108 frovatriptan metoclopromide 1109 frovatriptandomperidone 1110 frovatriptan prochlorperazine 1111 frovatriptanpromethazine 1112 frovatriptan chlorpromazine 1113 frovatriptantrimethobenzamide 1114 frovatriptan ondansetron 1115 frovatriptangranisetron 1116 frovatriptan hydroxyzine 1117 frovatriptanacetylleucine 1118 frovatriptan monoethanolamine 1119 frovatriptanalizapride 1120 frovatriptan azasetron 1121 frovatriptan benzquinamide1122 frovatriptan bietanautine 1123 frovatriptan bromopride 1124frovatriptan buclizine 1125 frovatriptan clebopride 1126 frovatriptancyclizine 1127 frovatriptan dimenhydrinate 1128 frovatriptan diphenidol1129 frovatriptan dolasetron 1130 frovatriptan meclizine 1131frovatriptan methallatal 1132 frovatriptan metopimazine 1133frovatriptan nabilone 1134 frovatriptan oxyperndyl 1135 frovatriptanpipamazine 1136 frovatriptan scopolamine 1137 frovatriptan sulpiride1138 frovatriptan tetrahydrocannabinol 1139 frovatriptanthiethylperazine 1140 frovatriptan thioproperazine 1141 frovatriptantropisetron 1142 frovatriptan droperidol 1143 frovatriptan haloperidol1144 frovatriptan prochloperazine 1145 frovatriptan metoclopramide 1146frovatriptan diphenhydramine 1147 frovatriptan cannabis 1148frovatriptan midazolam 1149 frovatriptan lorazepam 1150 frovatriptanhyoscine 1151 frovatriptan dexamethasone 1152 frovatriptan emetrol 1153frovatriptan propofol 1154 rizatriptan promethazine 1155 rizatriptanaprepitant 1156 rizatriptan dronabinol 1157 rizatriptan perphenazine1158 rizatriptan palonosetron 1159 rizatriptan trimethyobenzamide 1160rizatriptan metoclopromide 1161 rizatriptan domperidone 1162 rizatriptanprochlorperazine 1163 rizatriptan promethazine 1164 rizatriptanchlorpromazine 1165 rizatriptan trimethobenzamide 1166 rizatriptanondansetron 1167 rizatriptan granisetron 1168 rizatriptan hydroxyzine1169 rizatriptan acetylleucine 1170 rizatriptan monoethanolamine 1171rizatriptan alizapride 1172 rizatriptan azasetron 1173 rizatriptanbenzquinamide 1174 rizatriptan bietanautine 1175 rizatriptan bromopride1176 rizatriptan buclizine 1177 rizatriptan clebopride 1178 rizatriptancyclizine 1179 rizatriptan dimenhydrinate 1180 rizatriptan diphenidol1181 rizatriptan dolasetron 1182 rizatriptan meclizine 1183 rizatriptanmethallatal 1184 rizatriptan metopimazine 1185 rizatriptan nabilone 1186rizatriptan oxyperndyl 1187 rizatriptan pipamazine 1188 rizatriptanscopolamine 1189 rizatriptan sulpiride 1190 rizatriptantetrahydrocannabinol 1191 rizatriptan thiethylperazine 1192 rizatriptanthioproperazine 1193 rizatriptan tropisetron 1194 rizatriptan droperidol1195 rizatriptan haloperidol 1196 rizatriptan prochloperazine 1197rizatriptan metoclopramide 1198 rizatriptan diphenhydramine 1199rizatriptan cannabis 1200 rizatriptan midazolam 1201 rizatriptanlorazepam 1202 rizatriptan hyoscine 1203 rizatriptan dexamethasone 1204rizatriptan emetrol 1205 rizatriptan propofol

As to any pharmaceutically active agent disclosed in the foregoing Table1 or Table 2, it should be noted that any pharmaceutically acceptablesalt of the pharmaceutically active agent is within the variousembodiments of the present invention. Furthermore, non-limiting examplesof such pharmaceutically acceptable salts are disclosed herein.

While particular embodiments described herein have been shown anddescribed herein, such embodiments are provided by way of example only.Numerous variations, changes, and substitutions will now occur to thoseskilled in the art without departing from the invention. It should beunderstood that various alternatives to the embodiments of the inventiondescribed herein may be employed in practicing the invention. It isintended that the following claims define the scope of the invention andthat methods and structures within the scope of these claims and theirequivalents be covered thereby.

What is claimed:
 1. A solid oral pharmaceutical composition, comprising:a. a first plurality of particulates, wherein each particulate of thefirst plurality of particulates comprises an opioid analgesic, whereinthe opioid analgesic is tramadol or a pharmaceutically acceptable saltthereof; and b. a second plurality of particulates, wherein eachparticulate of the second plurality of particulates comprises anantiemetic, wherein the second plurality of particulates is formulatedfor immediate release, and wherein the antiemetic reduces or eliminatesan adverse effect of the opioid analgesic.
 2. The solid oralpharmaceutical composition of claim 1, wherein the adverse effect of theopioid analgesic is nausea or vomiting.
 3. The solid oral pharmaceuticalcomposition of claim 1, wherein the tramadol or the pharmaceuticallyacceptable salt thereof is present in an amount of about 1 mg to about100 mg.
 4. The solid oral pharmaceutical composition of claim 1, whereinthe tramadol or the pharmaceutically acceptable salt thereof is presentin an amount of 37.5 mg, 50 mg, or 100 mg.
 5. The solid oralpharmaceutical composition of claim 1, wherein the pharmaceuticallyacceptable salt of the tramadol is tramadol hydrochloride.
 6. The solidoral pharmaceutical composition of claim 1, wherein the antiemetic ispromethazine or a pharmaceutically acceptable salt thereof, orondansetron or a pharmaceutically acceptable salt thereof.
 7. The solidoral pharmaceutical composition of claim 6, wherein the promethazine orthe pharmaceutically acceptable salt thereof is present in an amount ofabout 0.5 mg to about 60 mg.
 8. The solid oral pharmaceuticalcomposition of claim 6, wherein the promethazine or the pharmaceuticallyacceptable salt thereof is present in an amount of about 6.25, about 10mg, about 12.5 mg, or about 25 mg.
 9. The solid oral pharmaceuticalcomposition of claim 6, wherein the promethazine is present in an amountof about 5.5 mg, about 11 mg, or about 22 mg.
 10. The solid oralpharmaceutical composition of claim 6, wherein the pharmaceuticallyacceptable salt of the promethazine is promethazine hydrochloride. 11.The solid oral pharmaceutical composition of claim 6, wherein thepharmaceutically acceptable salt of the ondansetron is ondansetronhydrochloride.
 12. The solid oral pharmaceutical composition of claim 1,wherein the solid oral pharmaceutical composition only contains twoactive agents.
 13. The solid oral pharmaceutical composition of claim 1,wherein the solid oral pharmaceutical composition comprises more thanone antiemetic.
 14. The solid oral pharmaceutical composition of claim1, wherein the solid oral pharmaceutical composition comprises one ormore excipients.
 15. The solid oral pharmaceutical composition of claim14, wherein the one or more excipients comprises: carnauba wax,crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropylmethylcellulose, mannitol, sodium hydroxide, sodium stearyl fumarate,talc, titanium dioxide, glyceryl monostearate 40-50, methacrylic acidcopolymer type C, polysorbate 80, sugar spheres, triethyl citrate,microcrystalline cellulose, hypromellose, croscarmellose sodium,magnesium stearate, stearic acid, sodium starch glycolate, or yellowferric oxide.
 16. The solid oral pharmaceutical composition of claim 1,wherein the solid oral pharmaceutical composition is in a capsule dosageform.
 17. A method for treatment of pain and reduction or prevention ofan adverse effect of an opioid analgesic, comprising administering to asubject in need thereof the solid oral pharmaceutical composition ofclaim
 1. 18. The method of claim 17, wherein the solid oralpharmaceutical composition is administered once, twice, or three timesdaily.